Hubble Telescope has captured a spectacular laser-like jet from a young star https://teslaxnews.com/hubble-telescope-has-captured-a-spectacular-laser-like-jet-from-a-young-star/
Day: 03/13/2022
COMPLETE GUIDE TO DIABETES-FRIENDLY SUGAR SUBSTITUTES
Today, it is easier than ever to cook and bake with sugar substitutes thanks to the wide variety of products available.
It wasn’t so long ago that most available sugar substitutes had strong off-flavors or, even worse, unfortunate gastrointestinal effects. (Check out the hilarious and horrifying review comments on this Amazon listing for the maltitol syrup-sweetened sugar-free gummy bears to see why the fear is very real.)
Nowadays there are so many options that it’s tough to know where to begin. How do they impact blood glucose? Are they easy on one’s stomach?
Some of these sweeteners have been widely available for decades, and others have gained popularity only recently.
A note: we have excluded popular sugar alternatives like agave syrup and coconut sugar. These may or may not be healthier than pure sugar, but they definitely have an identical blood sugar impact. This article will concentrate on sweeteners that do not provoke a blood sugar increase, and are therefore of special interest for people managing diabetes. That said, some of the sweeteners on this list are more diabetes-friendly than others, depending on what your personal needs are.
Check them out:
The New Sugar Substitutes
If you’re new to low-carb, you might not be aware of how many good new options there are for sugar alternatives.
Allulose:
Allulose may be our favorite zero-carb sweetener. The reasons are simple:
- Of every alternative sweetener we’ve tried, it tastes the best, which is to say that it tastes the most like true sugar. There is no aftertaste, no chemical flavor, no strange mouthfeel issues.
- It appears to have zero impact on blood sugar.
The science backs us up. In a 2018 study, allulose was actually found to slightly reduce the blood sugar of people with type 2 diabetes.
Allulose is not as sweet as sugar, but it works extremely well in baking recipes, and can even be turned into caramel.
Monk Fruit:
Monkfruit powder is another sugar alternative that we can recommend highly. It’s extremely popular in the keto community, especially when sold under the brand name Lakanto. The Lakanto company sells monk fruit sugar in multiple varieties, including brown sugar, granulated white sugar, powdered white sugar, and has a range of products, from maple sugar and chocolate sauce to brownie mixes.
Monk fruit comes from the lo han guo fruit, found in China. It does not impact blood glucose and does not seem to cause gastrointestinal symptoms in users. It’s much sweeter than sugar, so a little goes a long way. Low-carb bakers love the way it behaves in recipes.
Users should be aware that monk fruit products often contain a smaller amount of erythritol, for an improved flavor profile and usability.
Erythritol:
You’ll find this under many brands, most notably as Swerve. You can find granular, powdered, and brown sugar versions of erythritol, often formulated so as to offer a 1:1 replacement for sugar, making it easy to use for baking. Many popular low-carb or sugar-free recipes use Swerve.
Erythritol is a sugar alcohol. It is almost completely calorie-free and has no known impact on blood sugar.
PubChem states erythritol is two times as sweet as sucrose. While most people seem to tolerate it well, there are some reports of eaters experiencing gas or bloating, so it may be smart to watch how much you include in your diet.
Stevia:
Stevia is a newly popular alternative sweetener. You can find it in grocery stores as SweetLeaf, Pyure, Stevia in the Raw, and several other brands. Derived from the leaves of a plant native to South America, stevia is an all-natural sweetener that is several hundred times sweeter than sugar, according to the FDA. It is calorie-free and won’t raise blood sugar.
Stevia is divisive because many tasters find that it has a bitter aftertaste. Many low-carb eaters absolutely love it, though. If you’re buying low-sugar packaged foods that use stevia, be sure to check the ingredients, because it’s often combined with sugar.
There are actually different types of stevia, and one of our staff members strongly prefers a type called “Reb A,” which is made from only a certain extra-delicious part of the plant. If you’ve tried stevia and haven’t liked it, it might be worth looking for the Reb A variety.
Xylitol:
Xylitol is another sugar alcohol: it’s about as sweet as sucrose but lower in calories. It does raise blood glucose a little bit, which may make it a less optimal choice than its cousin erythritol. PubChem explains that xylitol is a five-carbon sugar alcohol that can be found naturally in many fruits and vegetables.
This sugar alcohol may cause gastrointestinal distress in some individuals at a certain threshold intake. It may be possible that once the body acclimates to the sweetener, more can be consumed with no unwanted side effects.
Xylitol is often found in candy and sugar-free gum because it inhibits the growth of bacteria in the mouth.
Beware: xylitol is extremely toxic to dogs, so probably not ideal for a pet owner.
Traditional Sugar Substitutes
You’re probably already familiar with the flavor of these – most of them have been ubiquitous for decades. In our opinion, the alternative sugars below are more likely to have strange flavors and chemically aftertastes, and they’re also less likely to be useful in low-carb baking recipes. But many people love them! And they also probably won’t raise your blood sugar.
Aspartame:
Found on the market as NutraSweet and Equal. According to the American Cancer Society, it is about 200 times sweeter than sugar and is not for those with phenylketonuria disease. It’s also calorie-free and does not raise blood sugar but is not recommended for use in cooking or baking.
Maltitol:
Maltitol is a sugar alcohol commonly used as a way to make foods “sugar-free.” It doesn’t make foods “carbohydrate-free” however, as it still affects blood glucose somewhat. An analysis on PubChem references a study that found that Malitol has 38% the blood sugar impact of pure sugar, and that it was absorbed more slowly. However, beware: this chemical is known to provoke gastrointestinal problems.
Saccharin:
Sold as Sweet and Low, Sweet Twin, Sweet’N Low, and Necta Sweet. According to the FDA, saccharin was discovered in 1879. It is 200-700 times sweeter than sugar and is not as popular as it used to be, due to its bitter aftertaste and difficulty for use in baking.
Sorbitol:
According to the PubChem Chemistry Database, “Sorbitol is a sugar alcohol found in fruits and plants with diuretic, laxative and cathartic property.” Also, it contains “one-third fewer calories and 60 % the sweetening activity of sucrose and is used as a sugar replacement in diabetes.” As you can see, sorbitol can be a laxative, and still raises blood sugar. Be aware of this when choosing sorbitol!
Sucralose:
This is most commonly known as the brand name Splenda. Sucralose is calorie-free and doesn’t raise blood sugar. It can be tricky to bake with due to how sweet it is (about 600 times sweeter than sugar).
Use What Works for You
When choosing a sugar substitute, your goal is to enjoy the flavor as much as possible while maintaining steady blood sugar levels and avoiding unpleasant side effects. Your own experience will be unique. Some people are sensitive to some of these sweeteners, and some are not, so individual results have to be prioritized. It’s also possible that you’ll have different blood sugar responses than predicted in this article. And in matters of taste, of course, there can be no disputes.
se, sugar alcohols, sugar substitute, swerve sweetener, xylitol.
Cannabinoids for Medical Use
Abstract
Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.
Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.
Data Sources Twenty-eight databases from inception to April 2015.
Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.
Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.
Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.
Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.
Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
Cannabis is a generic term used for drugs produced from plants belonging to the genus Cannabis.1 It is one of the most popular recreational drugs; worldwide, an estimated 178 million people aged 15 to 64 years used cannabis at least once in 2012.2 Cannabis was included as a controlled drug in the United Nations’ Single Convention on Narcotic Drugs, held in 1961,3 and its use is illegal in most countries.
Medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. Cannabinoids can be administered orally, sublingually,or topically; they can be smoked, inhaled, mixed with food, or made into tea. They can be taken in herbal form, extracted naturally from the plant, gained by isomerisation of cannabidiol, or manufactured synthetically.4 Prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.4 Some countries have legalized medicinal-grade cannabis for chronically ill patients. Canada and the Netherlands have government-run programs in which specialized companies supply quality-controlled herbal cannabis.5 In the United States, 23 states and Washington, DC (May 2015), have introduced laws to permit the medical use of cannabis6; other countries have similar laws. The aim of this systematic review was to evaluate the evidence for the benefits and adverse events (AEs) of medical cannabinoids across a broad range of indications.
This review followed guidance published by the Centre for Reviews and Dissemination and the Cochrane Collaboration.7,8 We established a protocol for the review (eAppendix 1 in Supplement 1).
Randomized clinical trials (RCTs) that compared cannabinoids with usual care, placebo, or no treatment in the following indications were eligible: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis (MS) or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, intraocular pressure in glaucoma, or Tourette syndrome. These indications were prespecified by the project funders, the Swiss Federal Office of Public Health. If no RCTs were available for a particular indication or outcome (eg, long-term AEs such as cancer, psychosis, depression, or suicide), nonrandomized studies including uncontrolled studies (such as case series) with at least 25 patients were eligible.
Identification and Selection of Studies
Twenty-eight databases and gray literature sources were searched from inception to April 2015 without language restriction (Embase search strategy and details of databases searched available in eAppendix 2 in Supplement 2). The search strategy was peer reviewed9 by a second information specialist. Reference lists of included studies were screened. Search results and full-text articles were independently assessed by 2 reviewers; disagreements were resolved through consensus or referral to a third reviewer.
Data Collection and Study Appraisal
We extracted data about baseline characteristics and outcomes (patient-relevant and disease-specific outcomes, activities of daily living, quality of life, global impression of change, and specified AEs). For dichotomous data such as number of patients with at least 30% improvement in pain, we calculated the odds ratio (OR) and 95% CI. For categorical data, we extracted details about each category assessed and the numbers of patients with an outcome in each category. Continuous data such as the Ashworth spasticity score10 were extracted as means and SDs at baseline, follow-up, and the change from baseline and used to calculate mean differences with 95% CIs. Results (mean difference, 95% CIs, and P values) from the between-group statistical analyses reported by the study were also extracted. All relevant sources were used for data extraction including full-text journal articles, abstracts, and clinical trial registry entries. Where available, the journal article was used as the primary publication because it had been peer reviewed.
RCTs were assessed for methodological quality using the Cochrane Risk of Bias tool.11 If at least one of the domains was rated as high, the trial was considered at high risk of bias. If all domains were judged as low, the trial was considered at low risk of bias. Otherwise, the trial was considered as having unclear risk of bias. Data extraction and risk-of-bias assessment were performed independently by 2 reviewers; disagreements were resolved by a third reviewer.
Clinical heterogeneity was assessed by grouping studies by indication, cannabinoid, and outcome. If there were 2 or more trials within a single grouping, data were pooled using random-effects meta-analysis.12 For continuous outcomes, we analyzed the mean difference in change from baseline; if this was not reported and could not be calculated from other data, we used the mean difference at follow-up.13 For dichotomous data, we used the OR. In order to avoid double counting, we selected a single data set from each study to contribute to the analysis. For studies evaluating multiple interventions, we selected the intervention or dose that was most similar to the other interventions being evaluated in the same analysis. Heterogeneity was investigated using forest plots and the I2 statistic. Where data were considered too heterogeneous to pool or not reported in a format suitable for pooling (eg, data reported as medians), we used a narrative synthesis.
Sensitivity analyses were used to assess the statistical effect of trial design. The primary analysis included only parallel-group trials, results from crossover trials were included in an additional analysis. For the analysis of AEs, data for all conditions were combined. We conducted stratified analyses and meta-regression to investigate whether associations varied according to type of cannabinoid, study design (parallel group vs crossover trial), indication (each of the indication categories included in this report), comparator (active vs placebo), and duration of follow-up (<24 hours, 24 hours-1 week, >1 week-4 weeks, >4 weeks) for the outcome of any AE. Statistical analyses were performed using Stata statistical software (version 10).
GRADE (Grading of Recommendations Assessment, Development and Evaluation) was used to rate the overall quality of the evidence for risk of bias, publication bias, imprecision, inconsistency, indirectness, and magnitude of effect. The GRADE ratings of very low–, low-, moderate-, or high-quality evidence reflect the extent to which we are confident that the effect estimates are correct.14
The searches identified 23 754 hits (records) of which 505 were considered potentially relevant, based on title and abstract screening, and obtained as full-text studies. A total of 79 studies (6462 participants), available as 151 reports, were included; 3 studies (6 reports) were included in multiple indication categories (Figure 1). Thirty-four studies were parallel-group trials (4436 participants), and 45 were crossover trials (2026 participants). Four studies were available only as an abstract,15–18 a further 3 were available only as abstracts19–21 but with additional details available on trial registries including full results in one,19 and details of 2 trials (including full trial results) were available only as trial registry entries22,23; all other trials were reported in full-length journal articles. Where reported, the proportion of participants who were men ranged from 0% to 100% (median, 50% [57 studies]), and the proportion of white participants ranged from 50% to 99% (median, 78% [18 studies]). Publication dates ranged from 1975 to 2015 (median, 2004 [with one-third of trials published before 1990]). Studies were conducted in a wide range of countries. A variety of cannabinoids were evaluated and compared with various different active comparators or placebos; most active comparators were included in the nausea and vomiting indication (Table 1). eAppendices 3 to 12 in Supplement 1 provide an overview of the included studies and their findings.
Four (5%) trials were judged at low risk of bias, 55 (70%) were judged at high risk of bias, and 20 (25%) at unclear risk of bias (eAppendix 13 in Supplement 2). The major potential source of bias in the trials was incomplete outcome data. More than 50% of trials reported substantial withdrawals and did not adequately account for this in the analysis. Selective outcome reporting was a potential risk of bias in 16% of trials. These studies did not report data for all outcomes specified in the trial register, protocol, or methods section or changed the primary outcome from that which was prespecified. Most studies reported being double-blinded but only 57% reported that appropriate methods had been used for participant blinding and only 24% reported that outcome assessors had been appropriately blinded.
Full results from included studies are presented in eAppendices 3-12 in Supplement 2; pooled results and GRADE ratings are presented in Table 2.
Nausea and Vomiting Due to Chemotherapy
Nausea and vomiting due to chemotherapy was assessed in 28 studies (37 reports; 1772 participants).15,16,24–58 Fourteen studies assessed nabilone and there were 3 for dronabinol, 1 for nabiximols, 4 for levonantradol, and 6 for THC. Two studies also included a combination therapy group of dronabinol with ondansetron or prochlorperazine. Eight studies included a placebo control, 3 of these also included an active comparator, and 20 studies included only an active comparator. The most common active comparators were prochlorperazine (15 studies), chlorpromazine (2 studies) and domperidone (2 studies). Other comparators (alizapride, hydroxyzine, metoclopramide and ondansetron) were evaluated in single studies (Table 1). Of all 28 studies, risk of bias was high for 23 or unclear for 5. All studies suggested a greater benefit of cannabinoids compared with both active comparators and placebo, but these did not reach statistical significance in all studies. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids (dronabinol or nabiximols) than placebo (OR, 3.82 [95% CI, 1.55-9.42]; 3 trials). There was no evidence of heterogeneity for this analysis (I2 = 0%) and results were similar for both dronabinol and nabiximols.
Appetite Stimulation in HIV/AIDS Infection
Appetite stimulation in HIV/AIDS was assessed in 4 studies (4 reports; 255 participants).59–62 All studies assessed dronabinol, 3 compared with placebo (1 of which also assessed marijuana), and 1 compared with megastrol acetate. All studies were at high risk of bias. There was some evidence that dronabinol is associated with an increase in weight when compared with placebo. More limited evidence suggested that it may also be associated with increased appetite, greater percentage of body fat, reduced nausea, and improved functional status. However, these outcomes were mostly assessed in single studies and associations failed to reach statistical significance. The trial that evaluated marijuana and dronabinol found significantly greater weight gain with both forms of cannabinoid when compared with placebo.59 The active comparison trial found that megastrol acetate was associated with greater weight gain than dronabinol and that combining dronabinol with megastrol acetate did not lead to additional weight gain.60
Chronic pain was assessed in 28 studies (63 reports; 2454 participants).19,20,22,23,63–120 Thirteen studies evaluated nabiximols, 4 were for smoked THC, 5 for nabilone, 3 for THC oromucosal spray, 2 dronabinol, 1 vaporized cannabis (included 2 doses), 1 for ajuvenic acid capsules, and 1 for oral THC. One trial compared nabilone with amitriptyline64; all other studies were placebo controlled. One of these studies evaluated nabilone as an adjunctive treatment to gabapentin.121 The conditions causing the chronic pain varied between studies and included neuropathic pain (central, peripheral, or not specified; 12 studies), 3 for cancer pain, 3 for diabetic peripheral neuropathy, 2 for fibromyalgia, 2 for HIV-associated sensory neuropathy, and 1 study for each of the following indications: refractory pain due to MS or other neurological conditions, for rheumatoid arthritis, for noncancer pain (nociceptive and neuropathic), central pain (not specified further), musculoskeletal problems, and chemotherapy-induced pain.
Two studies were at low risk of bias, 9 at unclear risk, and 17 at high risk of bias. Studies generally suggested improvements in pain measures associated with cannabinoids but these did not reach statistical significance in most individual studies.
The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids than with placebo (OR, 1.41 [95% CI, 0.99-2.00]; 8 trials; Figure 2). One trial assessed smoked THC77 and reported the greatest beneficial effect (OR, 3.43 [95% CI, 1.03-11.48]), and 7 trials assessed nabiximols (Figure 2). Pain conditions evaluated in these trials were neuropathic pain (OR, 1.38 [95% CI, 0.93-2.03]; 6 trials) and cancer pain (OR, 1.41 [95% CI, 0.99-2.00]; 2 trials), with no clear differences between pain conditions. Nabiximols was also associated with a greater average reduction in the Numerical Rating Scale (NRS; 0-10 scale) assessment of pain (weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), brief pain inventory-short form, severity composite index (WMD, −0.17 [95% CI, −0.50 to 0.16]; 3 trials), neuropathic pain scale (WMD, −3.89 [95% CI, −7.32 to −0.47]; 5 trials), and the proportion of patients reporting improvement on a global impression of change score (OR, 2.08 [95% CI, 1.21 to 3.59]; 6 trials) compared with placebo. There was some evidence to support this based on continuous data but this was not consistent across trials. There was no difference in average quality-of-life scores as measured by the EQ-5D health status index (WMD, −0.01 [95% CI, −0.05 to 0.02]; 3 trials) between nabiximols and placebo. Two of the studies included in the meta-analysis for the NRS (0-10 scale) assessed patients with cancer pain, all other studies assessed patients with neuropathic pain. There were no clear differences based on cause of pain in the meta-analysis of NRS. Sensitivity analyses that included crossover trials showed results consistent with those based on parallel-group trials alone.
Spasticity Due to MS or Paraplegia
Fourteen studies (33 reports; 2280 participants) assessed spasticity due to MS or paraplegia.17,19,65,87,91,122–149 Eleven studies (2138 participants) included patients with MS and 3 included patients with paraplegia (142 participants) caused by spinal cord injury. Six studies assessed nabiximols, 3 for dronabinol, 1 for nabilone, 4 for THC/CBD (2 of these also assessed dronabinol), and 1 each for ECP002A and smoked THC. All studies included a placebo control group; none included an active comparator. Two studies were at low risk of bias, 5 were at unclear risk of bias, and 7 were at high risk of bias. Studies generally suggested that cannabinoids were associated with improvements in spasticity, but this failed to reach statistical significance in most studies. There were no clear differences based on type of cannabinoid. Only studies in MS patients reported sufficient data to allow summary estimates to be generated. Cannabinoids (nabiximols, dronabinol, and THC/CBD) were associated with a greater average improvement on the Ashworth scale for spasticity compared with placebo, although this did not reach statistical significance (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials; Figure 3). Cannabinoids (nabilone and nabiximols) were also associated with a greater average improvement in spasticity assessed using numerical rating scales (mean difference, −0.76 [95% CI, −1.38 to −0.14]; 3 trials). There was no evidence of a difference in association according to type of cannabinoid for either analysis. Other measures of spasticity also suggested a greater benefit of cannabinoid but did not reach statistical significance (Table 2). The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo (OR, 1.44 [95% CI, 1.07 to 1.94]; 3 trials); this was supported by a further crossover trial of dronabinol and oral THC/CBD that provided continuous data for this outcome.132 Sensitivity analyses that included crossover trials showed results consistent with those based on parallel group trials alone.
No studies evaluating cannabinoids for the treatment of depression fulfilled inclusion criteria. Five studies included for other indications reported depression as an outcome measure; 4 evaluated chronic pain and 1 evaluated spasticity in MS patients.67,73,75,80,129 One trial assessed dronabinol (2 doses), 3 assessed nabiximols, and 1 assessed nabilone. Two studies were rated as having unclear risk of bias and 3 as having high risk of bias. Three studies suggested no difference between cannabinoids (dronabinol and nabiximols) and placebo in depression outcomes. One parallel-group trial that compared different doses of nabiximols with placebo reported a negative effect of nabiximols for the highest dose (11-14 sprays per day) compared with placebo (mean difference from baseline, 2.50 [95% CI, 0.38 to 4.62]) but no difference between placebo and the 2 lower doses.67
One small parallel-group trial, judged at high risk of bias, evaluated patients with generalized social anxiety disorder.150 The trial reported that cannabidiol was associated with a greater improvement on the anxiety factor of a visual analogue mood scale (mean difference from baseline, −16.52; P value = .01)compared with placebo during a simulated public speaking test. Additional data about anxiety outcomes provided by 4 studies (1 parallel group) in patients with chronic pain also suggested a greater benefit of cannabinoids (dronabinol, nabilone, and nabiximols) than placebo but these studies were not restricted to patients with anxiety disorders.73–75,80
Two studies (5 reports; 54 participants) evaluated cannabinoids (nabilone) specifically for the treatment of sleep problems. One was a parallel-group trial judged at high risk of bias. This reported a a greater benefit of nabilone compared with placebo on the sleep apnea/hypopnea index (mean difference from baseline, −19.64; P value = .02). The other was a crossover trial judged at low risk of bias in patients with fibromyalgia and compared nabilone with amitriptyline. This suggested that nabilone was associated with improvements in insomnia (mean difference from baseline, −3.25 [95% CI, −5.26 to −1.24]) and with greater sleep restfulness (mean difference from baseline, 0.48 [95% CI, 0.01 to 0.95]). Nineteen placebo-controlled studies included for other indications (chronic pain and MS) also evaluated sleep as an outcome.22,23,65,67–69,75,76,79–81,87,88,123–125,129–131 Thirteen studies assessed nabiximols, 1 for nabilone, 1 for dronabinol, 2 for THC/CBD capsules, and two assessed smoked THC (one at various doses). Two of the studies that assessed nabiximols also assessed oral THC and the trial of dronabinol also assessed oral THC/CBD. There was some evidence that cannabinoids may improve sleep in these patient groups. Cannabinoids (mainly nabiximols) were associated with a greater average improvement in sleep quality (WMD, −0.58 [95% CI, −0.87 to −0.29]; 8 trials) and sleep disturbance (WMD, −0.26 [95% CI, −0.52 to 0.00]; 3 trials). One trial assessed THC/CBD, all others assessed nabiximols, results were similar for both cannabinoids.
Psychosis was assessed in 2 studies (9 reports; 71 participants) judged at high risk of bias, which evaluated cannabidiol compared with amisulpride or placebo.21,151–158 The trials found no difference in mental health outcomes between treatment groups.
One very small crossover trial (6 participants)159 judged at unclear risk of bias compared tetrahydrocannabinol (THC; 5 mg), cannabidiol (20 mg), cannabidiol (40 mg) oromucosal spray, and placebo. This trial found no difference between placebo and cannabinoids on measures of intraocular pressure in patients with glaucoma.
Movement Disorders Due to Tourette Syndrome
Two small placebo-controlled studies (4 reports; 36 participants)160–163 suggested that THC capsules may be associated with a significant improvement in tic severity in patients with Tourette syndrome.
Data about AEs were reported in 62 studies (127 reports). Meta-regression and stratified analysis showed no evidence for a difference in the association of cannabinoids with the incidence of “any AE” based on type of cannabinoid, study design, indication, comparator, or duration of follow-up15,16,18,22–26,28–31,33–38,41,42,44–47,51,57,58,60,62,64–69,72–85,87,88,123–127,129–131,159,160,162; further analyses were conducted for all studies combined. Figure 4 shows the results of the meta-analyses for the number of participants experiencing any AE compared when compared with controls, stratified according to cannabinoid. Cannabinoids were associated with a much greater risk of any AE, serious AE, withdrawals due to AE, and a number of specific AEs (Table 3). No studies evaluating the long-term AEs of cannabinoids were identified, even when searches were extended to lower levels of evidence.
We conducted an extensive systematic review of the benefits and AEs associated with medical cannabinoids across a broad range of conditions. We included 79 RCTs (6462 participants), the majority of which evaluated nausea and vomiting due to chemotherapy or chronic pain and spasticity due to MS and paraplegia. Other patient categories were evaluated in fewer than 5 studies.
Most studies suggested that cannabinoids were associated with improvements in symptoms, but these associations did not reach statistical significance in all studies. Based on the GRADE approach, there was moderate-quality evidence to suggest that cannabinoids may be beneficial for the treatment of chronic neuropathic or cancer pain (smoked THC and nabiximols) and spasticity due to MS (nabiximols, nabilone, THC/CBD capsules, and dronabinol). There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy (dronabinol and nabiximols), weight gain in HIV (dronabinol), sleep disorders (nabilone, nabiximols), and Tourette syndrome (THC capsules); and very low-quality evidence for an improvement in anxiety as assessed by a public speaking test (cannabidiol). There was low-quality evidence for no effect on psychosis (cannabidiol) and very low-level evidence for no effect on depression (nabiximols). There was an increased risk of short-term AEs with cannabinoid use, including serious AEs. Common AEs included asthenia, balance problems, confusion, dizziness, disorientation, diarrhea, euphoria, drowsiness, dry mouth, fatigue, hallucination, nausea, somnolence, and vomiting. There was no clear evidence for a difference in association (either beneficial or harmful) based on type of cannabinoids or mode of administration. Only 2 studies evaluated cannabis.59,77 There was no evidence that the effects of cannabis differed from other cannabinoids.
MARIJUANA AND DIABETES: WHAT YOU NEED TO KNOW
Medical views and public opinions on cannabis (marijuana) have come a long way in the last several decades. Today, medicinal and recreational use of the plant and its derivatives are quickly gaining both acceptance and popularity.
What do people with diabetes need to know about using marijuana and cannabis products?
This article summarizes the major effects of cannabis and derived compounds on the physiology and various health conditions of people with diabetes.
Marijuana Laws in the United States
Please note that cannabis and many of its associated products remain illegal at the federal level. Anything written in this article is for informational purposes only and is not intended to serve as medical advice.
According to The National Organization for the Reform of Marijuana Laws (NORML), twenty-two US states and territories have (at least in part) “have passed laws allowing for the personal possession and consumption of cannabis by adults.” During the summer of 2021, Connecticut, New Mexico, and Virginia joined the party. A larger number of decriminalized cannabis possession and/or approved of medical marijuana.
Medicinal Uses of Cannabis
Reports of medicinal cannabis use date back thousands of years, and many studies into the plant’s medical potential are being conducted today. Generally speaking, medical authorities have come to recognize an increasing number of health benefits.
How does it work? Briefly, our bodies have what is referred to as an endocannabinoid system—that is, the specific cellular receptors that can interact with several different compounds that are found in marijuana and can affect a variety of physiological processes. As can be seen in the diagrams below, these receptors are present in many organs and tissues in humans.
Image credit: CANNA foundation
Cannabis contains many different compounds. The two major active compounds are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Researchers note that “available research indicates that the main two compounds, d-9-THC and CBD, whilst having similar effects in certain domains, also have almost opposite effects to one another in other aspects.” This highlights why specific preparations (e.g., CBD only) may be especially useful for treating a particular health condition.
Which health conditions may benefit from the use of cannabis or its derivatives? Since the endocannabinoid system can affect numerous processes, there are many conditions that can be targeted.
Some major conditions that have been proposed for targeting include:
- Anorexia
- Autoimmune Diseases (Rheumatoid Arthritis, Multiple Sclerosis, Inflammatory Bowel Disease)
- Cancers
- Cardiovascular Disease
- Glaucoma
- Liver Disease
- Nausea
- Nephropathy
- Neuropathy
- Neurodegenerative Diseases (e.g., Parkinson’s, Alzheimer;’s, Huntington’s)
- Obesity
- Pain
- Psychiatric Disorders
So, marijuana can affect a variety of organs and exerts both physical and psychological effects.
Many of these uses are already approved in some or all states where medicinal marijuana is legal. As can be seen, some of these conditions (e.g., neuropathy, nephropathy, cardiovascular disease, obesity) are more prevalent in people with diabetes, which may make medicinal cannabis use more useful in this population.
In fact, at least one study reported on the benefits of CBD for the treatment of diabetic cardiomyopathy, while other research has shown that the endocannabinoid system is intimately involved in the development of many diabetes-associated complications, and highlights that several clinical trials have recently explored targeting cannabinoid receptors for treatment. More recent research summaries indicate that cannabis use is an effective treatment for neuropathy, and may even be superior to existing medications. However, additional long-term, larger studies are needed.
Marijuana and Blood Glucose Management
Can cannabis affect blood glucose control? And what should individuals with diabetes take into consideration to stay safe?
Potential Effects on Blood Glucose Levels
When it comes to the overall effects of marijuana or its components on blood glucose levels at any specific time of use, no conclusive research is available. Many variables affect blood glucose levels and can include food consumption, medication use, activity, anxiety levels, etc. This means that it’s very important for the individual to self-monitor their blood glucose levels to stay safe during cannabis use.
Anecdotally, many members of the diabetes community believe that (unlike alcohol) cannabis has very little direct effect on blood sugar. (The “munchies” that may result, however, are a different story.)
Interestingly, some research has suggested that marijuana users tend to be thinner than non-users and that users may be less likely to develop type 2 diabetes. Another study suggested that “chronic cannabis smoking was associated with visceral adiposity and adipose tissue insulin resistance but not with hepatic steatosis, insulin insensitivity, impaired pancreatic β-cell function, or glucose intolerance.”
At this time, it is difficult to form concrete conclusions due to the multitude of intersecting variables in population studies, and additional research is needed to shed more light on these topics.
What to Look Out For
Of course, any person with diabetes should always be on the lookout for hypoglycemia and hyperglycemia and make the appropriate adjustments. Marijuana can affect one’s mental state, so it is important to prepare ahead of time, by setting alarms to check blood glucose levels, or by having another individual with you who knows about diabetes and can help you check your blood glucose and make the appropriate treatment decisions, if necessary.
If there’s a good reason to be cautious, it’s one study that suggested an association between marijuana use and a higher likelihood of developing diabetic ketoacidosis (DKA), a serious and life-threatening complication of diabetes. However, a causal relationship is not clear, the findings are limited by small sample size, and confounding variables, such as income and education level.
It’s unclear whether or not long-term cannabis use has a significant effect on glycemic control, for better or for worse. While some studies have shown that patients who used marijuana also happened to have a significantly higher A1C level, it’s impossible to state whether or not cannabis itself contributed to the comparative lack of diabetes control. Other studies have shown the opposite.
The American Heart Association recently published a statement warning that cannabis use appears to be linked cardiovascular risk factors (and has few or zero demonstrated cardiovascular benefits). However, the science on this topic is still extremely shaky, and the organization hopes that better studies will be undertaken in the future.
A Warning for Regular Cannabis Users with Type 1 Diabetes
If you use cannabis regularly (daily or almost daily) and have type 1 diabetes, there is one specific health issue that you need to be aware of.
Regular cannabis users occasionally experience vomiting and abdominal pain, especially in the morning, and many sufferers report that their symptoms are substantially relieved by hot baths or showers. The condition is called cannabis hyperemesis syndrome, and although it’s often described as rare, there is some evidence that as many as one-third of regular cannabis users experience it. If you sometimes take hot baths to relieve discomfort, pain, nausea, or vomiting, you have likely experienced cannabis hyperemesis syndrome yourself. As cannabis is usually thought to relieve nausea, some people with this syndrome may be unaware of its cause.
This condition is especially dangerous for people with type 1 diabetes, because it can cause a unique and potentially deadly type of ketosis that somewhat resembles diabetic ketoacidosis (DKA). Although patients do not develop the highly acidic blood characteristic of DKA, the symptoms are otherwise almost identical.
This knowledge is brand new. In December of 2021, researchers in the journal Diabetes Care described and named this phenomenon for the first time: “hyperglycemic ketosis due to cannabis hyperemesis syndrome (HK-CHS).”
If these symptoms sound familiar, please be extra cautious, and seek medical help if you experience them again. The best way to prevent “hyperglycemic ketosis due to cannabis hyperemesis syndrome” is to cease using cannabis products.
Conclusions
As with using any new medication or recreation drug (such as alcohol), it is imperative that people with diabetes remain in control of their condition by checking their blood glucose levels frequently and adjusting accordingly. If a patient is prescribed medicinal cannabis, it is important to discuss any concerns with a healthcare provider ahead of time and to be extra diligent about checking blood glucose levels frequently during use.
Patients with type 1 diabetes should also be extra cautious about regular cannabis use, due to the possibility of hyperglycemic ketosis due to cannabis hyperemesis syndrome.
Today, cannabis remains illegal at the federal level, but a gray area is increasingly emerging, for both medicinal and recreational use, as more and more states pass new legislature. We will update this article as more research is conducted, and as state and federal laws are updated.
References
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Botulinum Toxin for the Treatment of Neuropathic Pain
Abstract
Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves inhibiting the release of inflammatory mediators and peripheral neurotransmitters from sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, and peripheral neuralgia. The purpose of this review is to summarize the experimental and clinical evidence of the mechanism by which BoNT acts on various types of neuropathic pain and describe why BoNT can be applied as treatment. The PubMed database was searched from 1988 to May 2017. Recent studies have demonstrated that BoNT injections are effective treatments for post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain, such as poststroke pain and spinal cord injury.
Keywords: botulinum toxin, neuropathic pain, neuropathic pain treatment
1. Introduction
Botulinum toxin (BoNT) has been used for decades in the treatment of diseases, such as dystonia or seizures, and cosmetic treatments. BoNT is useful in conditions such as strabismus because it causes long lasting but reversible paralysis via the administration of small amounts locally [1,2]. As BoNT purification technology develops, the range of use of this drug has been expanded, and the number of Food and Drug Administration (FDA)-approval diseases has also increased. Common to these applications is the fact that BoNT is absorbed from the neuromuscular junction or parasympathetic axon terminal to the motor neuron terminal because the toxin is responsible for the release of acetylcholine. It is important to note that these effects are not systematically redistributed but only localized. Numerous reports suggest that local administration of BoNT has a significant effect on neuropathic pain.
For a long time, the analgesic effect of Botulinum toxin A (BoNT-A) was considered to be due to the effect of muscle relaxation [3,4,5]. However, recent studies using BoNT in neuropathic pain models have demonstrated that BoNT has an analgesic effect independent of muscle relaxation by demonstrating dissociation of the duration of muscle relaxation and duration of pain relief [6].
In this paper, we investigate the mechanism of BoNT in neuropathic pain by examining the effects of the drug for intractable neuropathic pains, such as postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, trigeminal neuralgia, phantom limb pain, spinal cord injury-induced neuropathic pain, and central poststroke pain.
2. Structure of Botulinum Toxin
BoNT is protein group produced by anaerobic bacteria called Clostridium botulinum, which has approximately 40 subtypes. However, seven serotypes are typically noted based on antigen specificity. Botulinum toxin A (BoNT-A) and B (BoNT-B) are the most commonly used drugs. Particularly, BoNT-A type has a molecular weight of approximately 900,000. BoNT-A is a double chain protein. The light chain (LC) is active, whereas the heavy chain (HC) is not active. BoNT binds to the acceptor at the nerve end and enters the nerve ending by receptor-mediated endocytosis. LC binds to the exogenous protein involved in exocytosis and breaks down the peptide bond of the protein transporter to block exocytosis and acetylcholine secretion. The C-terminal receptor-binding domain, which constitutes the heavy chain of BoNT, binds to ganglioside receptors and specific proteins on the cell membrane. This binding induces endocytosis of HC-LC. In general, acetylcholine binding to the acetylcholine receptor of the motor endplate is necessary for muscle contraction. At this time, the acetylcholine exocytosis process is necessary in presynaptic membrane. The normal acetylcholine exocytosis process requires three proteins: the synaptosomal associated protein-25 kDa (SNAP-25), syntaxin, and the vesicle-associated membrane protein (VAMP)/synaptobrevin in the presynaptic membrane. These proteins are called soluble N-ethylmaleimide (SNARE) proteins. As a zinc-dependent endoprotease, the LC of BoNT cleaves intracellular SNARE. This cleavage interferes with SNARE-mediated protein transport and transmitter release, blocking muscle innervation at the neuromuscular junction and resulting in flaccid paralysis [7,8]. This effect of BoNT LC is dependent on the serotype, but it persists from days to months [9,10].
BoNT-A and BoNT-B are effective in neuropathic pain. Mice can be treated with nerve ligation to induce mononeuropathy and cisplatin to induce polyneuropathy. BoNT-B improves allodynia and hyperalgesia [11]. A clinically reported case report demonstrates that BoNT-B improves pain and symptoms in complex regional pain syndrome (CRPS) patients with a lumbar sympathetic block [12].
3. Mechanism of Action of Botulinum Toxin for Neuropathic Pain (Experimental Study)
BoNT also reduces and alters neuropathic pain in several animal models via the following mechanisms. BoNT inhibits the secretion of pain mediators (substance P, glutamate, and calcitonin gene related protein (CGRP)) from the nerve endings and dorsal root ganglions (DRG), reduces local inflammation around the nerve endings, deactivates the sodium channel, and exhibits axonal transport. We will review the various mechanisms by which BoNT reduces neuropathic pain (Figure 1).
(A) Noxious stimuli cause inflammation through the release of neuropeptides and inflammatory mediators, which can cause peripheral sensitization. This action also occurs in DRG, dorsal horn of spinal cord and can lead to central sensitization. Botulinum toxin (BoNT) inhibits the release of pain mediators in peripheral nerve terminal, DRG, and spinal cord neuron, thereby reducing the inflammatory response and preventing the development of peripheral and central sensitization. Symbols; SP, substance P; CGRP, calcitonin gene related protein; DRG, dorsal root ganglion; (B) The hyperexcitability and spontaneous action potential mediated by the Na channel in peripheral sensory neuron contribute to the pathophysiology of neuropathic pain. BoNT can control neuropathic pain by blocking the Na channel; (C) Some of the BoNT appear to retrograde transport along the axons. SNAP-25 is cleaved in the dorsal horn of the spinal cord and central nuclei after a small amount of BoNT is administered to the periphery, thereby boosting the retrograde transport of BoNT.
3.1. BoNT Inhibits the Release of Pain Mediators from the Peripheral Nerve Terminal, DRG, and Spinal Cord Neuron
The effect of BoNT on the secretion of sensory neurotransmitters has been documented in several animal models. BoNT reduces normal CGRP release and capsaicin-induced DOA secretion and has additional effects on the TRPV1 pathway [13]. According to Meng et al., in a rat trigeminal ganglion sensory peptidergic neuron cell culture model, BoNT cleaves neuronal SNARE and blocks neurotransmitter secretion [14]. Durham et al. also reported a prophylactic advantage in migraine headaches via blocking the release of neuropeptides, such as CGRP from the trigeminal ganglion neuronal culture [15].
Fan et al. demonstrated that BoNT significantly reduces TRPV1 protein levels. Several studies demonstrated that TRPV1 plays a crucial role in arthritis pain, and this article examined the causal relationship between the antinociceptive effect of BoNT and the expression of TRPV1 in DRG of rats with arthritic pain. No significant changes in TRPV1 mRNA levels were observed via RT-PCR performed with different BoNT doses (1, 3, and 10 U); However, BoNT or TRPV1 protein levels were significantly decreased. This paper demonstrates the antinociceptive mechanism of BoNT by reducing TRPV1 expression by inhibiting plasma membrane trafficking after intra-articular administration [16].
3.2. BoNT Reduces Inflammation
Cyclophosphamide (CYP) was injected into the bladder of rats to induce CYP-induced cystitis, and HCL was injected into the bladder to induce acute injury. The bladder was harvested and compared with the Sham group. The cells were cultured in a solution containing BoNT to compare neurotransmitters. CGRP and substance P were significantly increased in the acute injury group compared with the control group, and substance P was significantly increased in the CYP-induced cystitis group. After exposure to BoNT, neurotransmitter levels were significantly reduced. In this article, we found that BoNT has an anti-inflammatory effect on chronic inflammation and acute injury [17]. In a chronic arthritis dog model, intraarticular BoNT injections are effective for up to 12 weeks [18,19]. The anti-inflammatory effect of BoNT reduces the release of peripheral neurotransmitters and inflammatory mediators.
However, the effects are debated. Rojecky et al. injected carrageenan and capsaicin into the hindpaw of the rat, and rats were treated with BoNT five days before injection. No significant differences in edema and plasma protein extravasation were noted between the group injected with BoNT and the group without BoNT [20]. In addition, Sycha et al. reported that the BoNT group and the control group had no direct effect on acute, noninflammatory pain in the group treated with BoNT upon skin exposure to Ultraviolet B [21]. Chuang et al. measured cyclooxygenase-2 (COX-2) levels in the capsaicin-induced prostatitis model. COX-2 is a key enzyme that is an important mediator of inflammation and pain. COX-2 expression was induced as assessed by Western blotting or immunostaining. Inflammation was induced upon injection of capsaicin into the prostate of an adult male rat. Another group was pretreated with 20 U BoNT one week before injection of capsaicin. The expression of COX-2 was reduced in spinal sensory and motor neurons and the prostate in the pretreatment group [22].
BoNT also decreases local inflammation around the nerve terminal. According to the report of Cui et al., BoNT was administered to the footpads in formalin-inflammatory pain model rats. The antinociceptive effect started 5 h after BoNT treatment and persisted for greater than 12 days. In addition, edema was reduced, but no localized muscle weakness was observed. Formalin-induced glutamate release was also significantly reduced. This finding demonstrates that local inflammation around the nerve endings is reduced in the absence of obvious muscle weakness [23].
3.3. BoNT Deactivates Sodium Channels
BoNT also deactivates the sodium channel. Na current stimulates numerous cellular functions, such as transmission, secretion, contraction, and sensation. BoNT-A changes the Na current of a neuronal excitable membrane, which is different from that of local anesthetics, tetrodotoxin, and antiepileptic drugs that completely control the Na current via a concentration-dependent manner [24].
3.4. BoNT Exhibits Axonal Transport
BoNT exhibits axonal transport function from the periphery to the CNS, and administering BoNT to the facial and trigeminal nerve causes SNAP-25 cleavage in the central nuclei. In addition, a small amount of BoNT was injected into the hind limb, confirming the cleavage of the SNAP-25 in the ventral horn and the dorsal horn of the ipsilateral spinal cord, thereby demonstrating the retrograde axonal transport function of BoNT [25]. In addition, the BoNT effect on both sides has been reported after injecting BoNT on one side [26,27,28]. In animal studies, the anti-nociceptive effect of BoNT was studied in paclitaxel-induced peripheral neuropathy. The withdrawal nociceptive reflex was reduced after paclitaxel injection into the hind paw of the rat. BoNT was injected into one side, but the analgesic effect was observed on both sides. Diffusion into blood circulation may affect the central nervous system, but the dose was too low to cause systemic side effects. BoNT is also too large to pass the BBB, so the theory that BoNT is transmitted from the periphery to the central nervous system through the axon is possible [28]. To prevent retrograde axonal transport, Rojecky et al. confirmed the antinociceptive effect of unilateral transport of the axonic transport blocker colchicine in the ipsilateral sciatic nerve [26], which also demonstrated the retrograde axonal transport of BoNT.
However, this notion is controversial. Tang et al. injected 125I-radiolabeled free BoNT into the gastrocnemius muscle of rats and rabbit eyelids and observed BoNT in various tissues at different time points. In both rabbits and rats, systemic effects were absent, and most of the toxins remained in the injection site. The authors concluded that most of the BoNT remained near the injection site and did not cause systemic toxicity [29].
Whether BoNT is transported retrograde from the injection site remains controversial. However, retrograde axonal transport has been demonstrated in numerous papers. Marinelli et al. analyzed the expression of cl-SNAP-25 from the nerve endings of the hind paw to the spinal cord after applying BoNT to the periphery. Immunostained cl-SNAP-25 was detected in all tissues. Additional experiments were performed to assess whether the growth state of Schwann cells interacts with BoNTs. As a result, BoNT regulated the proliferation of Schwann cells to inhibit acetylcholine release. This result demonstrates retrograde trafficking of BoNT [30].
4. Clinical Study of Botulinum Toxin for Neuropathic Pain
4.1. Trigeminal Neuralgia
A review of the efficacy of Botulinum toxin (BoNT) on trigeminal neuralgia (TN) has been reported in approximately 11 cases, including three RCT papers. This review includes the largest number of clinical trials for neuropathic pain for BoNT. In a randomized, double-blind, placebo-controlled study of 42 patients, Wu et al. performed a parallel design with intradermal or submucosal injection of 75 U of BoNT-A in 22 patients. Twenty patients in the control group received 1.5 mL saline. In the BoNT group, 68.8% of patients had a visual analog scale (VAS) reduction of greater than 50%. In the control group, a VAS reduction of greater than 50% was noted in 15% of the patients [31]. In addition, a randomized, double-blind, placebo-controlled study was performed in 84 adults with TN by Zhang et al. 28 control subjects were treated with saline, 27 with 25 U BoNT-A, and 29 with 75 U BoNT-A. The response rates in the 25 U and 75 U groups were 70.4% and 86.2%, respectively, which were significantly different from the control group (32.1%). However, no significant differences were noted between the two groups [32]. According to Zuniga et al., 20 patients received 50 U of BoNT-A, and 16 controls received the same dose of saline. VAS was 4.9 vs. 6.63 at two months follow-up. No significant differences were noted between the two groups. At three months, there was a significant difference at 4.75 vs. 6.94 [33].
Prospective, open, and case series for trigeminal neuralgia are reported in three studies. According to Bohluli et al., 15 TN patients were administered 50–100 U of BoNT-A in the trigger zone without any special injection mode. All patients reported a reduction in pain frequency and VAS score [34]. Zuniga et al. reported 12 trigeminal neuralgia patients who underwent subcutaneous injection in the trigger zone, and a reduction in VAS lasting greater than two months was noted in 10 patients [35]. Turk et al. also reported that injection of 50 U BoNT-A at 1.5–2 cm depth around the zygomatic arch was performed in eight patients, and the incidence of pain and VAS were reduced in all patients [36]. The above papers are summarized in Table 1.
Table 1
Botulinum toxin for trigeminal neuralgia.
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized double-blind, placebo-controlled | 42 | Intradermal, submucosal (75 U/saline 1.5 mL) | 50% VAS reduction 68.8% (Botulinum toxin (BoNT) group) 15% (Control) | [31] |
| Randomized, double-blind, placebo-controlled | 84 (27 BoNT 25 U, 29 BoNT 75 U, 28 control) | Intradermal, submucosal (25 U/75 U/saline 1 mL) | Visual analog scale (VAS) reduction 70.4% (25 U) vs. 86.2% (75 U) vs. 32.1% (Control) | [32] |
| Randomized, double-blind, placebo-controlled | 36 (20 BoNT, 16 control) | Intramuscular (50 U/saline 1 mL) | VAS (BoNT vs. Control) 4.9 vs. 6.63 (2 months) 4.75 vs. 6.94 (3 months) | [33] |
| Prospective, open, case series | 15 | Injected at the trigger zones (50–100 U) | All patients improved frequency and severity of pain attacks | [34] |
| Prospective, open, case series | 12 | Subcutaneous (20–50 U) | VAS reduced lasting more than 2 months in 10 patients. | [35] |
| Prospective, open, case series | 8 | Around zygomatic arch, 1.5–2 cm depth (50 U per point, total 100 U) | Incidence of pain and VAS were reduced in all patients. | [36] |
4.2. Postherpetic Neuralgia
Two BoNT RCTs for postherpetic neuralgia (PHN) have been reported. Xiao et al. performed a randomized, double-blind, placebo-controlled study of 60 patients with PHN. The following study groups were included: the BoNT group, 0.5% lidocaine group, and 0.9% saline group. These patients were treated 5 U/mL BoNT-A, 0.5% lidocaine and 0.9% saline in the affected dermatome, respectively. Follow-up was performed at one day, seven days, and three months after drug administration. The BoNT group exhibited significantly improved VAS and sleep quality compared with the other two groups [37]. In addition, Apalla et al. performed a randomized, double-blind, placebo-controlled study on 30 adults with PHN, and the affected sites were divided into a chessboard of 5 U BoNT-A per injection. Thirteen of the 15 patients had a VAS reduction of at least 50% lasting approximately 16 weeks and a significantly reduced the sleep score [38]. Previously, there were reports on the antinociceptic effect of BoNT. Liu et al. reported that the VAS decreased from 10 to 1 after BoNT-A injection into the lesion, and the effect persisted for 52 days [39]. Sotiriou et al. reported assessed a case series of three patients. The affected site was divided into a chessboard form using a total of 100 U BoNT-A with 5 U injected at each point. The VAS started to decrease in three days and continued to decrease for greater than two months [40]. These papers are summarized in Table 2.
Table 2
Botulinum toxin for postherpetic neuralgia.
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized, double-blind, placebo-controlled | 60 | Subcutaneous BoNT 5 U, 0.5% lidocaine, 0.9% saline per site | Significantly VAS pain score was decreased and sleep time improved | [37] |
| Randomized, double-blind, placebo-controlled | 30 | Divided into chessboard 5 U per site | 50% VAS reduction of 13 patients | [38] |
| Case report | 1 | Fan pattern injection 100 U | VAS decrease from 10 to 1 Lasted for 52 days | [39] |
| Case series | 3 | Divided into chessboard 5 U per site (100 U) | VAS decrease and continued to 2 months | [40] |
4.3. Post-Surgical Neuralgia
Four reports on the efficacy of BoNT on post-surgical neuralgia, including RCT articles, have been published. RCT articles include post-herpetic neuralgia and post-traumatic neuralgia. According to Ranoux et al., 29 patients with focal painful neuropathy and mechanical allodynia were included in a randomized, double-blind, placebo-controlled study. Up to 20–190 U BoNT-A was injected into the pain site intradermally. The injections reduced VAS, burning sensation, and allodynic brush sensitivity and improved QOL [41]. Layeeque et al. also observed postoperative pain. In 48 breast cancer patients subject to mastectomy, 22 patients were treated with BoNT-A in the pectoralis major, serratus anterior, and rectus abdominis muscle, and 26 control group patients were not treated. The group treated with BoNT reported improved post-operative pain, and post-operative analgesic use was significantly reduced. In addition, the tissue expander was removed from one patient in the BoNT group and five patients in the control group. The BoNT group did not complain of any particular complications [42]. A case report described satisfactory results from subcutaneous injection of BoNT-A in a 67-year-old patient with post-thoracotomy pain for more than two years postoperatively. The pain site was divided into 1-square centimeter. Then, 2.5 U of BoNT-A was injected into the middle, and 100 U BoNT-A was administered in total. The patient reported improved pain after five days, and pain relief persisted for up to 12 weeks [43]. According to Rostami et al., eight cancer patients with persistent focal pain were treated with surgery or radiotherapy. BoNT-A was injected intramuscularly or subcutaneously into the localized pain area. All patients reported significant VAS improvement, and a significant improvement in QOL was also noted [44]. The above studies are described in Table 3.
Table 3
Botulinum toxin for post-surgical neuralgia.
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized, double-blind, placebo-controlled | 29 (4 Postherpetic neuralgia, 25 Post-traumatic, post-surgical neuropathy) | Intradermal (20–190 U) | Decrease VAS, neuropathic nature pain and improve in quality of life | [41] |
| Prospective, non-randomized, placebo-controlled | 48 (22 BoNT, 26 control) | Intramuscular (100 U) | Post-operative pain and analgesic use was reduced | [42] |
| Case report | 1 | Subcutaneous Affected zone was drawn with divisions of approximately 1 cm2, 2.5 U per site (100 U) | Improvement in pain was about 50% as measured on the VAS and persisted at 12 weeks | [43] |
| Pilot, prospective | 8 | Intramuscular, subcutaneous (100 U) | All patients had VAS improvement | [44] |
4.4. Diabetic Neuropathy
Two randomized, double-blind, placebo-controlled studies used BoNT for pain control of diabetic neuropathy (DN). In a study of 20 DN patients, Yuan et al. reported that 4 U of BoNT-A per site (total 50 U) was administered to the dorsum of foot, and 44% of patients had a clear reduction in VAS lasting three months and improved sleep quality [45]. Ghasemi et al. conducted a study similar to the previous paper, except that the BoNT dose was 8–10 U per site in 40 DN patients. A decrease in neuropathic pain score (NPS) and Douleur Neuropathique 4 (DN4) scores were reported in that study [46]. A meta-analysis of these two articles concluded that DN has a significant association between BoNT and pain relief [47]. The above papers are described in Table 4.
Table 4
Botulinum toxin for diabetic neuropathy.
| Study Design | No. of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized, double-blind, placebo-controlled, cross-over trial | 20 | Intradermal 4 U per site at dorsum of foot (50 U per each foot) | 44.4% of the BoNT group experienced a reduction of VAS within 3 months. | [45] |
| Randomized, double-blind, placebo-controlled | 40 | Intradermal, dorsum of the foot, in a grid distribution pattern, total 12 sites 8–10 U per site | Decrease in neuropathic pain score and Douleur Neuropathique 4 | [46] |
4.5. Occipital Neuralgia
Kapural et al. retrospectively analyzed six patients injected with 50 U BoNT-A in the occipital nerve and found that the VAS was significantly reduced. Five patients exhibited pain relief lasting greater than four weeks [48]. Taylor et al. reported that 100 U of BoNT-A was administered to the occipital protuberance in the prospective, open, and case series. Improvement in sharp/shooting pain was noted, but no definite improvement in dull/aching pain was indicated [49]. Occipital neuralgia has been assessed in only two case series without an RCT article, so these studies are insufficient to prove the effectiveness of BoNT. The above papers are also described in Table 5.
Table 5
Botulinum toxin for occipital neuralgia.
| Study Design | No. of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Case series | 6 | Occipital nerve block 50 U for each block (100 U) | Significant VAS reduction and pain relief lasting >4 weeks | [48] |
| Prospective, open, case series | 6 | Greater and lesser occipital nerve block (100 U) | Improvement in sharp/shooting pain, no definite improvement in dull/aching pain | [49] |
4.6. Carpal Tunnel Syndrome
Breuer et al. conducted a randomized, double-blind, placebo-controlled study of 20 patients. In this study, 2,500 U of BoNT-B or saline was injected into hypothena muscle and tentorium associated with carpal tunnel. Tingling sensation, pain, and pain related to improved sleep were noted, but there was no significant difference compared with the control group [50]. In a prospective, open, pilot study of five patients, a total of 30 U of BoNT-A was injected intracarpally. Of the five patients, three reported insignificant pain relief, and none had electrophysiological changes [51]. These results suggest that the use of BoNT in carpal tunnel syndrome is not effective. These papers are described in Table 6.
Table 6
Botulinum toxin for carpal tunnel syndrome.
| Study Design | No. of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized, double-blind, placebo-controlled | 20 | Intramuscular, hypothena muscle, tentorium (2500 U) | No significant difference compared to the control group | [50] |
| Prospective, open, pilot | 5 | Intracapal 30 U for each carpal tunnel (60 U) | Three patients insignificant reduced pain, none had electrophysiological change. | [51] |
4.7. CRPS
Safarpour et al. reported that two patients with CRPS had a reduction of CRPS and myofascial pain with the intramuscular administration of 20 U BoNT-A per site and trigger point injection [52]. They also performed randomized, prospective, double-blind, placebo-controlled, open-label extension studies of BoNT in CRPS patients. Fourteen patients with CRPS were divided into the BoNT group (n = 8) and control group (n = 6). A total of 40–200 U (5 U per point) BoNT was administered to the affected area with allodynia. No difference was found between the interventional group and the placebo group, and this study was terminated early due to the intolerance of BoNT [53]. In another study, lumbar sympathetic block was performed in a randomized, double-blind, placebo-controlled crossover study. Patients received standard LSGB on one side, and 10 mL of 0.5% bupivacaine was used. The same patient was injected with a crossover (another side) injection of 75 U BoNT-A in 10 mL of 0.5% bupivacaine. The control group has a median of 10 days, whereas the BoNT group has a median of 71 days [54]. In a case series published by Choi et al., two patients who experienced short-term effects on the lumbar sympathetic block were injected with 5000 U of BoNT-B in 0.25% levobupivacaine with a lumbar sympathetic block. VAS, allodynia, edema, coldness, and analgesic drug usage were reduced [12]. In a prospective, open case series of 11 patients with CRPS symptoms in upper limb girdle muscles, a total of 300 U of BoNT-A was administered to the pain-related muscles at 25–50 U. All patients exhibited improved VAS, allodynia, hyperalgesia, and skin color after 6–12 weeks [55]. In a retrospective, uncontrolled, unblended study of 37 patients, as a result of administering a total of 100 U of BoNT-A (10–20 U per pain site), 97% of patients reported pain reduction, and the average pain score decreased by 43% [56]. Except for one negative study, positive results have been published. However, these studies include a low class papers, and the effect of BoNT in CRPS patients has not been proven. These papers are summarized in Table 7.
Table 7
Botulinum toxin for complex regional pain syndrome (CRPS).
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Case series | 2 | Intramuscular Trigger point 20 U per site | Reduction of CRPS pain and myofascial pain | [52] |
| Randomized, prospective, double-blind, placebo-controlled, and open-label extension | 14 (8 BoNT group, 6 control group) | Intradermal, subcutaneous Allodynia area 5 U per site (40–200 U) | No difference between BoNT group and placebo group, terminated study early. | [53] |
| Randomized, double-blind, placebo-controlled crossover | 9 (18 cases) | Lumbar sympathetic block 75 U BoNT + 0.5% bupivacaine/0.5% bupivacaine | Longer duration of pain reduction (BoNT vs. control/71 days vs. 10 days) | [54] |
| Case series | 2 | Lumbar sympathetic block 5000 U BoNT-B + 0.25% levobupivacaine | VAS and CRPS symptoms were reduced. | [12] |
| Prospective, open case series | 11 | Affected site, 25–50 U per site (300 U) | All patients had improved VAS, allodynia, hyperalgesia, and skin color after 6 to 12 weeks | [55] |
| Retrospective, uncontrolled, unblended | 37 | Affected site, 10–20 U per site (100 U) | The 97% patients reduced pain. (average pain reduction of 43%) | [56] |
4.8. Phantom Limb Pain
In a prospective, randomized, double-blind pilot study, 14 patients with phantom limb pain were treated with 50 U per site for a total of 250–300 U BoNT-A. In addition, a lidocaine and depomedrol mixture was administered at the focal tender point. VAS was assessed monthly in patients before and six months after treatment. Both groups reported improved pain. The BoNT group had an advantage over pain control during the 3–6 months, but phantom limb pain was not completely alleviated [57]. There is a case report in which the effect of BoNT was effective in reducing phantom limb pain for greater than 12 months. In total, 25 U of BoNT-A was injected into the trigger point of the stump at four sites, and the patient was able to reduce the pain medication given that the pain was significantly eliminated [58]. The effect of BoNT on phantom limb pain cannot be verified because only low-grade studies on phantom limb pain have been reported. The above papers are also listed in Table 8.
Table 8
Botulinum toxin for phantom limb pain.
| Study Design | No. of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Prospective, randomized, double-blind, pilot | 14 | Intramuscular/cutaneous/subcutaneous/neuroma (EMG guidance) 50 U per site (250–300 U) | Both groups improved pain and BoNT group had an advantage over pain control during 3–6 months but could not completely change phantom limb pain. | [57] |
| Case series | 3 | EMG guidance into points with strong fasciculation (500 U) | Phantom pain, pain medication could be reduced, the gait became more stable and the artificial limb was better tolerated. | [58] |
4.9. Spinal Cord Injury-Induced Neuropathic Pain
In a study of 40 patients with spinal cord injury-induced neuropathic pain, a randomized, double-blind, placebo-controlled design was used. In the BoNT group, 200 U BoNT-A was divided into 40 sites, and 4 mL of saline was administered to the control group in a similar manner. Pain intensities were assessed using VAS, the Korean version of the short-form McGill Pain Questionnaire (SF-MPQ), and the Korean version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire. The same procedure was performed at baseline and four and eight weeks. The BoNT group exhibited a statistically significant decrease in VAS at four and eight weeks compared with the placebo group, and SF-MPQ was also significantly reduced compared with the placebo group. However, there was no significant difference between the control group and the BoNT group in the Korean version of the WHOQOL-BREF, which assesses physical health, psychological social relationship, and environmental domains [59]. A similar paper was published in 2017, and a randomized, double-blind, placebo-controlled study was performed in 44 patients with spinal cord injury-induced neuropathic pain. The BoNT group received 200 U of BoNT-A at the pain site, and the control group received the same amount of saline at the pain site. Unlike the above paper, patients received the same treatment once daily for eight weeks. The primary outcome of pain was measured on a VAS scale, and the secondary outcome was measured by the SF-MPQ and the WHOQOL-BREF questionnaire. At four and eight weeks, both primary and secondary outcomes were measured and evaluated. No adverse effect was noted in both groups. VAS and SF-MPQ were significantly decreased in the BoNT group compared with placebo group at four and eight weeks, respectively. The difference from the above paper is that the WHOQOL-BREF also exhibited a statistically significant decrease compared with the placebo group [60].
In addition, there have been several case reports of neuropathic pain associated with spinal cord injury. Jabbari et al. reported that two patients who had burning pain and allodynia after spinal cord injury injected with 5 U of BoNT-A at 16–20 sites in the pain site maintained significant VAS reduction for greater than three months [61]. Han et al. mentioned that 20 U of BoNT-A was injected into 10 painful areas in patients with spinal cord injuries, and VAS was decreased from 96 to 23 [62]. The use of BoNT for spinal cord injury is considered to be effective based on a statistically significant RCT journal report. These papers are listed in Table 9.
Table 9
Botulinum toxin for spinal cord injury-induced neuropathic pain.
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Randomized, double-blind, placebo-controlled | 40 | Subcutaneous (200 U) | Significantly VAS was decreased at 4 and 8 weeks. | [59] |
| Randomized, double-blind, placebo-controlled | 44 | Subcutaneous (200 U) Once daily for 8 weeks | Significantly VAS was decreased at 4 and 8 weeks. | [60] |
| Case | 2 | Subcutaneous 5 U of BoNT at 16–20 sites | Significant VAS reduction for more than 3 months | [61] |
| Case | 1 | Subcutaneous 20 U of BoNT at 10 sites | VAS decreased from 96 to 23. | [62] |
4.10. Central Poststroke Pain
Poststroke patients often use BoNT due to poststroke spasticity. However, some recent reports have reported that BoNT is used for central poststroke pain control. Shippen et al. injected BoNT in patients with elbow flexor spasticity with central poststroke pain. The patients had severe neuropathic pain at the site of the spasticity and received 100 U BoNT-A of Biceps Brachii, 75 U Brachialis and 25 U Brachioradialis. After the second day, the pain was reduced, and the spasticity was improved one week after administration. The patients repeat BoNT every three months to control pain [63]. Barbosa et al. also published a case report in which an analgesic effect was obtained using BoNT-A in patients with central poststroke pain. In two patients with stroke, injection of BoNT-A 200 U into the affected area under EMG guidance resulted in a decrease in NRS after a 3-month follow-up [64]. A randomized, double-blind, placebo-controlled trial of 273 patients with poststroke spasticity was performed. In total, 74.3% of the patients had stroke-related pain, and 47.3% were suffering from greater than NRS 4. Patients were divided into two groups: BoNT-A and standard care vs. placebo and standard care. The degree of pain was compared 12 weeks from the baseline, and the BoNT group reported significantly less pain compared with the placebo group. The reduction in pain persisted for up to 52 weeks [65]. This is the first RCT assessing the control of neuropathic pain with BoNT in patients with poststroke spasticity. Therefore, BoNT may be effective in patients with central poststroke pain. The above papers are summarized in Table 10.
Table 10
Botulinum toxin for central poststroke pain.
| Study Design | Number of Patients | Method of Injection (Total Volume) | Result | Reference |
|---|---|---|---|---|
| Case | 1 | Intramuscular Biceps Brachii 100 U, Brachialis 75 U and Brachioradialis 25 U | Pain was reduced after 2 days, spasticity was improved after 1 week. | [63] |
| Case | 2 | Intramuscular Affected muscle (200 U) | NRS reduction for more than 3 months | [64] |
| Randomized, double-blind, placebo-controlled | 273 (139 BoNT, 134 control) | Intramuscular Dosing was determined by investigator, second injection was performed with an open label and at least 12 weeks after the first injection | Significantly VAS was decreased at 12 weeks and reductions in pain were sustained through Week 52. | [65] |
5. Adverse Effects
BoNT-A has minimal irreversible medical adverse effect. Regarding the use of BoNT in cervical dystonia, side effects, including neck muscle weakness, dysphagia, pain during swallowing, and flu-like symptoms, are rarely reported. The use of BoNT in blepharospasm and cerebral palsy is associated with unilateral or bilateral ptosis, hematoma, and lower limb weakness and pain. When BoNT is used in neuropathic pain, relatively minor complications, such as antibody formation and immune-related complications, are reported when a small amount of BoNT-A enters the circulatory system [66]. BoNT-B can also be used to obtain effective results when neutralizing antibodies are present in BoNT-A, and the effect is reduced. [67,68].
6. Conclusions
Before beginning BoNT therapy, patients with neuropathic pain require a careful assessment of functional limitations, goals, and expected outcomes. The guidelines of the American Academy of Neurology recommend the use of BoNT-A in neuropathic pain as follows. In postherpetic neuralgia, trigeminal neuralgia, and spinal cord injury-induced neuropathic pain, BoNT is effective (Level A) and BoNT is probably effective in post-surgical neuralgia, diabetic neuropathy, and central poststroke pain (Level B). In neuropathic pain, such as occipital neuralgia, CRPS, and phantom limb pain, a large and well-designed blinded and randomized controlled trial is needed to evaluate the effect of BoNT. The route of administration of BoNT is different for each article. There are no clinical guidelines for administration of BoNT for neuropathic pain. Most treatments are subcutaneous or intradermal, and BoNT is also injected intramuscularly or into the surrounding tissues. In some papers, BoNT is injected into the skin as a chessboard. In other studies, BoNT is directly injected into the nerve. In particular, the development of ultrasound technology can accurately inject drugs near the nerve, and BoNT injection near the nerve is emerging as an alternative method [69].
There is a need for comparative studies on whether these methods are effective and safe or which methods are more effective than others. In addition, studies should be carried out to compare the minimum doses that are effective. Large, well-designed clinical trials are needed to address these problems.
Conflicts of Interest
The authors declare no conflict of interest.
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HOW TO TREAT PAIN FROM DIABETIC NEUROPATHY
Are you struggling with pain in your feet, legs, or hands from diabetic neuropathy? This is an especially frustrating condition that is both under-assessed and undertreated. And for those that do seek relief, it’s typical to have to try many different treatments before hitting on a combination that works.
Diabetic neuropathy pain is exactly the sort of condition where you might need the wisdom of people that have been there before. We reviewed more than a hundred comments in our Facebook group and forum to get an idea of how our community, made up of regular people with diabetes, deals with this problem.
This article will explore both the mainstream science of neuropathy pain mitigation and the everyday advice of Diabetes Daily community members.
What is Diabetic Neuropathy?
Diabetic neuropathy is a type of nerve damage common in people with diabetes. Neuropathy can affect many parts of the body, including the digestive system, the heart, the eyes, the bladder, the sweat glands, and sexual organs.
The nerve damage that mostly affects the feet, hands, legs, and arms is referred to as peripheral neuropathy. This condition is often very uncomfortable, with patients feeling pain, tingling, burning, prickling, numbness, and complete loss of feeling in the extremities. The pain may be worse at night. These symptoms are generally noticed first in the feet.
Diabetic neuropathy, like other diabetes complications, is ultimately caused by chronic high blood sugars. If you’ve begun to notice the pain associated with this condition, you should visit your doctor or endocrinologist soon. Diabetic neuropathy may indicate that you are also at risk of other serious complications.
Blood Sugar Control
If there’s one treatment for neuropathic pain that the Diabetes Daily community can wholeheartedly endorse, it is optimal blood sugar control.
Diabetic neuropathy is primarily caused by high blood sugar. Achieving a lower, healthier blood sugar is the best way to address the root cause of neuropathy, and may offer both short- and long-term relief. It is unclear if nerve damage can be reversed, but further damage can be prevented through superior blood sugar control.
If there’s another good reason to prioritize blood sugar control, it’s the fact that diabetic neuropathy is an early warning sign of some very dangerous diabetes complications. The feet of a patient with neuropathy may be less capable of healing wounds, which can ultimately “lead to limb compromise, local to systemic infection, and septicemia, and even death.” Several of our community members have had terrifying battles with septicemia.
Prescription Drugs
Don’t hesitate to speak to your doctor about prescription medication for this condition. Pharmaceuticals don’t work for everyone, but they might work for you.
In our community, the most popular pharmaceutical treatment seems to be gabapentin (Neurontin). Gabapentin is an oral prescription medication that acts on the brain, changing the way that it perceives pain. It is also used as an anti-convulsant, to prevent seizures in patients with epilepsy and related conditions.
Your doctor is likely to start you on a low dose, and you may need to increase that dose in order to feel an effect, or if the condition gets worse.
Gabapentin doesn’t work for everyone. A rigorous study found that only 35% of study participants enjoyed significant pain reduction, compared to 21% who were given a placebo, and that “over half of those treated with gabapentin will not have worthwhile pain relief.”
Gabapentin can have side effects, including skin issues, dizziness, and drowsiness. A small minority of users experience intense mood changes that may include suicidal thoughts.
Lyrica (pregabalin) may be the second most popular drug neuropathic pain in our community. Lyrica is related to gabapentin, belonging to the same class of anti-convulsants.
The evidence suggests that Lyrica and other pregabalins have a similar impact to gabapentin. A large review concluded that “Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment.”
The American Academy of Neurology (AAN) officially recommends three other types of drugs for the treatment of diabetic neuropathy. These three are less commonly prescribed, and as a result, are less commonly discussed in our community:
- Serotonin-norepinephrine reuptake inhibitors (SNRIs), including duloxetine, venlafaxine, and desvenlafaxine. SNRIs are anti-depressants that are prescribed for a variety of mental health issues, including anxiety and obsessive-compulsive disorder. They can be effective in reducing neuropathic pain and, as a bonus, may improve mood and other quality of life factors.
- Tricyclic antidepressants (TCAs), such as amitriptyline, nortriptyline, and imipramine. TCAs are also anti-depressants, and have been used for decades. TCAs are considered “effective” in the treatment of neuropathic pain, but are associated with side effects, including weight gain.
- Sodium channel blockers (such as carbamazepine, oxcarbazepine, lamotrigine, valproic acid, lacosamide). Like gabapentinoids (including gabapentin and pregabalin), these drugs are used to prevent seizures. Sodium channel blockers are not often prescribed, perhaps due to the likelihood of side effects, but the AAN has concluded that they have a similar ability to reduce pain as the preceding drugs.
The AAN believes that the drugs named above are of roughly similar effectiveness, and that doctors should therefore make their recommendations based on “potential adverse effects, patient comorbidities, cost, and patient preference.”
The other important thing to note here is that none of these drugs is perfectly effective, and that doctors are completely unable to predict which drugs will work for which patients. Diabetic neuropathy is a mysterious condition, and experts don’t completely understand why drugs do and don’t work to reduce pain. It may take many months of experimentation with a series of pharmaceuticals to find a pill and a dose that works for you.
Finally, a word about opioids. These powerful painkillers are, in fact, the most commonly-prescribed treatment in the United States for diabetic neuropathy. However, they are not popular in the Diabetes Daily community. That may be for the best: experts from the AAN believe that the drugs should not be prescribed for this type of chronic pain. It seems that most doctors are unaware of that recommendation; a distressing 2020 study in the journal Pain found that most patients are prescribed opioids “before trying even one guideline-recommended medication for peripheral neuropathy,” and that far too many patients end up on chronic opioid therapy. The dreadful impact of opioid addiction is by now very well-known.
Mental Health and Sleep
It may sound surprising, but the American Academy of Neurology actually recommends that people with pain from diabetic neuropathy should seek treatment for sleep and mood disorders first, before they explore pain-relieving medication.
While mood or sleep improvements do not actually address the root cause of painful diabetic neuropathy, they do significantly alter our perception of pain.
It stands to reason that a well-rested and happy person is better equipped to deal with chronic pain. If that sounds too obvious, consider that people with diabetes suffer from both depression (and related mental health issues) and sleep disorders far more frequently than average, and that these conditions far too commonly go unrecognized and untreated.
The next time you see your healthcare provider, consider whether you should be discussing your sleep and mental health, in addition to your neuropathy pain and discomfort.
Topical Treatments
There is a bewildering variety of over-the-counter creams and sprays available for neuropathy pain. Experts are optimistic about the use of topical treatments, but scientific proof of their efficacy is a bit murky.
In the AAN guidance, four topical treatments were rated as “possibly more likely than placebo to improve pain.” Those treatments are:
- Capsaicin
- Nitrosense patches
- Citrullus colocynthis
- Glyceryl trinitrate spray
A different recent review identified many more chemicals that may be helpful, including even botox injections. This second review highlighted lidocaine and capsaicin patches as two therapies with particularly good data supporting their efficacy.
One brand that our community likes is Biofreeze, which uses menthol as its active ingredient. Biofreeze is available in many different application forms, including sprays, gels, patches, and wipes.
But to put it simply, nobody really knows which topical treatments work best, and what works for you may not work for someone else. It will probably take trial and error to find a product you like. We encourage you to work with your doctor to find good options.
Exercise
Exercise is a tricky subject for some people with neuropathic pain, because a workout itself may trigger that pain. There is also the fear that exercise is likely to cause problems for people with sensitive feet.
However, there is evidence that exercise is healthful for those damaged nerves. A 2014 review concluded that “it is critical to understand that routine exercise may not only help prevent some of those causes [of neuropathic pain], but that it has also proven to be an effective means of alleviating some of the condition’s most distressing symptoms.” And experts have argued that the benefits of exercise outweigh the risk of foot injuries.
Exercise can also be an important part of a holistic treatment plan for diabetic neuropathy. Even low-intensity exercise is known to help lower both blood sugar and cholesterol, prevent weight gain, and improve both mood and sleep, all of which means it will help combat both the root causes of neuropathic pain and your ability to tolerate pain.
Cannabis and CBD
When polling the Diabetes Daily community, perhaps the biggest surprise was how enthusiastically so many of our readers endorsed cannabis for neuropathic pain relief. Many have ranked it as their favorite way to alleviate or cope with the pain and discomfort.
Indeed, there is some evidence that cannabis can be effective. A small 2015 study found that “inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain.” A follow-up by the same team found a similar result.
Generally speaking, experts are somewhat hesitant. In 2021, the International Association for the Study of Pain announced that, due to a lack of good scientific evidence, it could not endorse the use of cannabis for pain relief. The organization also noted that there are important research gaps and much work to be done.
If medicinal-use cannabinoid products are allowed in your area, your doctor may be happy to write you a prescription. If adult-use cannabis is allowed, you don’t need a prescription. Nevertheless, please be aware that the legal status of cannabis use remains confusing in the United States. It is illegal at the federal level, but a gray area is increasingly emerging, for both medicinal and recreational use, as more and more states pass new legislature.
To learn more about cannabis and diabetes—including blood sugar effects and a special warning for patients with type 1 diabetes—please read our article, Marijuana and Diabetes, What You Need to Know.
Some of our community members also recommend CBD oil, either consumed or applied directly to the skin. Most medical authorities believe that the evidence in favor of CBD oil is extremely thin, and caution patients to be wary of anecdotes and marketing claims. Is CBD oil just snake oil? It’s impossible to say. Some of our community members believe it works, and there is some evidence that CBD oil can reduce neuropathic pain.
Elevating Feet
It is the feet, more than any other body part, that suffer most from peripheral neuropathy. Diabetes can lower the blood flow to the feet, which leads to all manner of issues, including slower wound healing and increased risk of infection.
Inadequate blood flow may contribute to nerve damage and pain in the feet. Elevating your feet may bring some pain relief.
When practical, put your feet up while sitting. Be sure to stand up, stretch your legs, and wiggle your feet and toes every once in a while. If the tingling, burning, and pain are at their worst when you’re in bed, experiment with elevating your feet by resting them on a pillow, even while you sleep.
Soaking Feet
Many people with diabetic neuropathy find fast relief from a good bath. Some go a step further, and include Epsom salts in their soaking ritual.
A 2020 study found that an electrical foot bath filled with saltwater offered significant pain reduction. (The warm water bath without salt had no effect).
But it is important to know that major diabetes authorities disagree with this advice, in part because a long soak may not be great for patients with vulnerable feet. The American Diabetes Association very plainly states: “don’t soak your feet.” If your feet are prone to slow-healing wounds, it may be wise to be careful with this remedy.
Compression Socks
Opinions differ on the wisdom of wearing compression socks. Some sources claim that these socks, which gently squeeze the lower legs, promote healthy blood flow. Others claim the exact opposite and say that compression socks restrict blood flow.
Compressions socks are most popular among people with diabetes that have foot and leg swelling issues. Studies have found that compression socks are effective in treating lower leg edema (swelling) without compromising circulation. We were not, however, able to find any published studies evaluating compression socks and pain from diabetic neuropathy.
Some of our community members find them useful for the treatment of neuropathic pain, but many experts think they’re a bad idea for people with diabetes. The National Institutes of Health tells people with diabetes foot issues: “do not wear tight socks.”
Alpha Lipoic Acid
Alpha lipoic acid (ALA) is a fatty acid and antioxidant that is found both in the human body and in many foods. It’s been proposed as an alternative treatment for many conditions, including neuropathic pain.
Several of our community members take ALA supplements (they should be easy to find in most pharmacies). ALA is theorized to improve “nerve blood flow, nerve conduction velocity, and several other measures of nerve function.” And there is some scientific evidence that ALA really does help to relieve neuropathic pain.
B Vitamins
B vitamins have a complex relationship with the human nervous system; too little or too much of certain B vitamins can directly cause nerve damage.
Some Diabetes Daily readers take a B vitamin supplement, and believe that it helps with their neuropathic pain. The science, though, is unclear. A review of 13 studies concluded that “the evidence is insufficient to determine whether vitamin B is beneficial or harmful,” but that the supplements were “generally well-tolerated.” There is some weak evidence that vitamin B12 may be helpful.
Massage
Whether they do it themselves, persuade a loved one, or hire a professional, several of our community members find relief from massage. Although the science on this isn’t exactly settled, a quick google search will show that there are many protocols out there for massage for pain relief from neuropathy.
We identified two studies that found significant pain reduction from aromatherapy massage, although it’s unclear if the aromatic oil or the massage was the critical element, or if they’re both necessary for relief. A 2016 study found that “Thai foot massage” achieved significant results, and a large 2019 meta-analysis found that Chinese acupressure massage, when combined with a Chinese medicinal footbath, also offered improvement.
Of course, you don’t really need a randomized controlled trial to know if a little foot rub feels good. This can be considered a nonpharmaceutical therapy with few downsides, one that is well worth a try.
When Nothing Works
Unfortunately, some of our community members have never found anything that helps relieve their pain. If that’s the case, we encourage you to re-prioritize blood sugar control and consider lifestyle changes that can promote stress reduction and good mental health.
There are also many resources out there for people that deal with chronic pain, such as the U.S. Pain Foundation, which has a wealth of information on coping mechanisms and self-management techniques. As the American Psychological Association states, “Mental and emotional wellness is equally important—psychological techniques and therapy help build resilience and teach the necessary skills for management of chronic pain.”
Takeaways
There are no easy answers for pain from diabetic neuropathy. Patients that do find some relief often use a combination of prescription medication, over-the-counter treatments, and non-medicinal techniques such as massage or foot elevation. Good blood sugar management is the only therapy that addresses the root cause.
If you have neuropathic pain, please seek treatment from a medical professional soon. The problem is better addressed sooner than later, and it may take some experimentation to find what works for you.
Read more about chronic pain, complications, foot pain, neuropathy, peripheral neuropathy.
Canada Authorizes First Plant-Based COVID-19 Vaccine
Canada has become the first country to authorize a plant-based COVID-19 vaccine.
Health Canada regulators said Thursday that Medicago’s two-dose vaccine can be given to ages 18-64 but added there’s too little data on the shots in ages 65 and older.
The decision was based on a study of 24,000 adults, which found that the vaccine was 71% effective at preventing COVID-19 overall and 75% effective against the Delta variant. However, the study was conducted before the Omicron variant emerged, The Associated Press reported.
The shot is the sixth COVID-19 vaccine to receive regulatory approval in Canada. Side effects were mild, including fever and fatigue.
Medicago uses plants to grow noninfectious virus-like particles, which mimic the spike protein of the coronavirus. The particles are removed from plant leaves and purified. Then another ingredient — an immune-boosting chemical called an adjuvant made by British drugmaker GlaxoSmithKline — is added to the shots.
Medicago, which is based in Quebec City, has agreed to supply up to 76 million doses to the Canadian government, Reuters reported. On Thursday, the company announced that it would fulfill the order “as soon as possible.”
Although numerous COVID-19 vaccines have been developed and approved worldwide, global health experts have said that additional vaccines could increase the global supply. Medicago intends to apply for approval of the shot in Japan, Reuters reported, and is discussing the vaccine with regulatory authorities in the U.S., Europe and Asia.
Medicago also plans to test the shot as a booster dose among children, Reuters reported, as is preparing to study an Omicron-specific version of the vaccine.
“We will, in the next several months, know how well our vaccine did against Omicron,” Brian Ward, the company’s medical officer, told CBC News.
Canada’s National Advisory Committee on Immunization will provide recommendations on the vaccine’s use in coming weeks.
Switching generic levothyroxine preparations does not affect thyroid hormone levels
Adults who switch generic levothyroxine preparations from one manufacturer to another do not have a difference in mean thyroid-stimulating hormone levels compared with those who do not switch, according to study data.
According to guidelines published by the American Thyroid Association in 2014, providers are advised to avoid switching among generic levothyroxine products from different manufacturers. Juan P. Brito, MD, MSc, associate professor of medicine and consultant in the division of endocrinology at the Mayo Clinic in Rochester, Minnesota, said the guidelines have led providers to prescribe brand-name levothyroxine for most adults with hypothyroidism because physicians are unable to keep track of when pharmacies switch generic products.
“We decided to do this study to test whether switching among generic levothyroxine products have any effect on thyroid hormone values,” Brito told Healio. “In those who switch, we don’t see an impact on thyroid hormone levels compared with people who did not switch. This sends a signal that switching is safe and keeping patients on generic levothyroxine doesn’t have a significant impact on thyroid hormone values.”
Brito and colleagues conducted a retrospective study of deidentified administrative claims data from 2008 to June 2019 in the OptumLabs Data Warehouse, a database that includes people enrolled in commercial insurance and Medicare Advantage programs across the U.S. Researchers included 15,829 adults who filled a generic levothyroxine prescription from Mylan, Sandoz or Lannett (mean age, 58.9 years; 73.4% women, 71.4% white). Adults with a stable prescription dose from the same manufacturer and a normal TSH level between 0.3 mIU/L and 4.4 mIU/L for at least 3 months were included in the analysis. TSH levels were collected from those who used the same generic prescription from a random fill date within a year of their first fill data, and from the date of switching for adults who changed preparations.
The findings were published in JAMA Internal Medicine.
Of the study cohort, 82.4% continued taking the same generic preparation during the study period, and 17.6% switched at least once. The 2,780 adults who switched were paired with an adult in the nonswitching group using propensity score-matching. Among the matched pairs, the percentage of adults with a normal TSH between 0.3 mIU/L and 4.4 mIU/L was similar between switchers (84.5%) and nonswitchers (82.7%). Similarly, the proportion of adults with markedly abnormal TSH levels of less than 0.1 mIU/L or greater than 10 mIU/L was similar for switchers (2.5%) and nonswitchers (3.1%). Mean TSH levels were 2.7 mIU/L in both groups.
In a subgroup of 364 adults receiving more than 100 g of levothyroxine daily, there was no significant difference between switchers and nonswitchers in the percentage of those with normal TSH levels. There were also no associations observed in sensitivity analysis.
Brito said the findings provide evidence for the ATA to update its recommendations to allow generic levothyroxine switching, noting the change can have a significant cost savings for patients currently taking brand-name preparations.
“Levothyroxine is one of the most prescribed medications in the U.S.,” Brito said. “It’s a huge market, and prescribing only brands is a significant expense to the health care system and the patients as well.
“Clinicians should not give patients a brand name just because they have concerns about switching,” Brito added. “They should revise the recommendation that we keep the patients on the same product.”
For more information:
Juan P. Brito, MD, MSc, can be reached at brito.juan@mayo.edu.
PERSPECTIVE
Jonathan D. Leffert, MD, FACP, FACE, ECNU
The study by Brito and colleagues on switching generic preparations of levothyroxine provides new data on this old topic and much food for thought. Brito and colleagues looked retrospectively at over 15,000 patients taking generic levothyroxine preparations to determine if switching preparations in this group of patients made a difference in their thyroid-stimulating hormone level. They found that among the switchers and nonswitchers, approximately 85% in each group maintained their TSH in the normal range. In each group, those with the highest and lowest TSH levels were also made up about the same proportion (3%). The conclusion of the study is that switching did not seem to make a difference in the TSH levels among patients on generic levothyroxine, and thus the current American Thyroid Association guidelines to avoid switching brand name preparations for generic preparations should be revised.
My initial concern with the conclusions of this study is this retrospective group included only patients on generic preparations, so it did not address the guideline concern about switching from brand name to generics. Secondly, the study did not include patients who are pregnant, a group in which trimester-specific TSH levels are required to ensure a good outcome. Other patients with specific thyroid disorders, such as those with thyroid cancer requiring suppression of their TSH and patients with secondary hypothyroidism due to pituitary disorders, also were not included in this cohort of patients.
Finally, Brito and colleagues previously examined this same database and found that 30% of the patients had normal thyroid function prior to initiating thyroid hormone. Because patients with normal pre-treatment TSH levels would not be likely to exhibit much in the way of change between different generic preparations, patients with normal thyroid function pre-treatment would more than likely have the same post-treatment thyroid function regardless of the preparation used to treat. In this present study, it was unclear if this database included only hypothyroid patients on treatment or patients with normal thyroid function on treatment.
As endocrinologists, we see patients with a wide variety of thyroid hormone replacement needs, which call for a range of thyroid hormone replacements. Our guidelines provide the flexibility to use thyroid hormone replacements based upon the clinical situation. These clinical situations, as stated in the guideline, include thyroid cancer patients, frail patients and those with congenital hypothyroidism. I would include pregnant patients and those with secondary hypothyroidism in which T4 levels would be most commonly used as a guide to therapy.
In order for guidelines to change, the evidence should be a moderate or high quality, which requires randomized clinical trials rather than retrospective studies, and the patient population should have documented hypothyroidism on replacement therapy.
In the final analysis, this study has raised some interesting questions regarding the important topic of switching between generic levothyroxine preparations. Before treatment guidelines can be changed, we will need more data on the special groups of patients, such as pregnant and thyroid cancer patients, studies that reinforce the equivalence of brand name and generic preparations of levothyroxine, and randomized controlled trials of hypothyroid patients on replacement therapy who have undergone switching of their therapy.
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
Past President, American Association of Clinical Endocrinologists
Endocrine Today Editorial Board Member
Maternal diet during pregnancy may impact development of asthma, allergies in offspring
A maternal diet with plenty of vegetables and limited fried, low-fiber and sugary foods may prevent asthma and allergies in offspring, according to a speaker at the American Academy of Allergy, Asthma & Immunology Annual Meeting.
Carina Venter, PhD, RD, associate professor of pediatrics in the section of allergy/immunology at Children’s Hospital Colorado and University of Colorado Denver School of Medicine, provided the latest data on the role the maternal diet during pregnancy may have on the infant microbiome and subsequent development of allergies and asthma, including research she has led on the topic.
Currently, it is recommended that a prenatal supplement with vitamin D be taken to reduce the risk for asthma and wheeze in offspring, Venter told Healio. Also, all allergy and pediatric medical societies recommend against avoiding food allergens during pregnancy to prevent food allergies in offspring, Venter said, although she added that the impact of maternal diet on other allergic diseases has so far been less conclusive.
Carina Venter
In a study published last year in Allergy, Venter and colleagues developed a maternal diet index during pregnancy — which included weighted measures of increased intake of vegetables and yogurt, and reduced intake of fried potatoes, rice/grains, red meats, pure fruit juice and cold cereals — to better assess the impact of maternal diet on offspring allergy outcomes.
Overall, greater intake of vegetables and yogurt appeared protective against development of offspring allergic disease, whereas the other food items were associated with greater risk in offspring.
Using these findings to inform the maternal diet index, researchers found that a one-unit increase in the index significantly reduced the likelihood of offspring allergic rhinitis (OR = 0.82; 95% CI, 0.72-0.94), atopic dermatitis (OR = 0.77; 95% CI, 0.69-0.86), asthma (OR = 0.84; 95% CI, 0.74-0.96) and wheeze (OR = 0.8; 95% CI, 0.71-0.9), but not food allergy (0.84; 85% CI, 0.66-1.08).
The researchers called their study the first to show a relationship between a maternal diet index and prevention of multiple allergic diseases in offspring but cautioned that more research is needed.
“Our data show that a diet with increased intake of vegetables and reduced intake of fried, low fiber and sugary foods is associated with reduced asthma, wheeze, allergic rhinitis and eczema by 4 years, and all allergies by 2 years of age,” Venter told Healio. “This needs to be confirmed in other cohorts and in randomized controlled trials.”
The researchers acknowledged that many of the foods in the index are known to impact the diversity and function of the gut microbiome, but how that affects the offspring microbiome, which in turn affects their allergy risk, remains to be elucidated.
“We have some preliminary data on how the maternal diet may affect the child’s microbiome and epigenetic profile, but many more studies are needed,” Venter said.
Despite these unknowns, maternal diet “is likely to play a role,” she added.
“Recent data indicate that the maternal diet can manipulate the maternal microbiome and subsequently the infant microbiome, but the exact effect in relation to allergy is still unclear,” she said.
Specifically, a study by Selma-Royo and colleagues, published in 2020 in European Journal of Nutrition, showed that maternal intake of saturated fats and monosaturated fatty acids appeared linked to intestinal markers and therefore likely indicates microbial transmission to the neonate.
Despite these data, a generalized diet that mothers can assume to reduce their offspring risk remains elusive.
It is clear that a diet filled with a variety of allergens in the infant’s first year of life has been shown to reduce their risk for later development of food allergies.
But pairing individual pregnant mothers with their optimal dietary intervention to prevent offspring allergic diseases remains a lofty goal.
“This statement is a ‘blue sky’ view of where we would like to be in the future, but more research data are required and we are not anywhere near clinical implementation yet,” Venter told Healio.
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Robotic Surgery in Oncology Gaining Traction
At the 2021 virtual American College of Surgeons Clinical Congress, a panel of experts discussed the benefits of robotic surgery in oncology. All panelists said more research was needed in comparing robotic approaches with open approaches.
Abhineet Uppal, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, in Houston, pointed out that 86% of patients are operated on at hospitals that don’t have robots. He said surgical complications for colorectal diseases are low regardless of the surgical approach that is used: open, laparoscopic or robotic. “Robotic surgery offers ergonomic and visualization advantages in confined spaces,” Dr. Uppal said. The learning curve for robotic surgery is significant, especially for surgeons without laparoscopic experience, he added.
Dr. Uppal said randomized data on the advantages of robotic surgery in colorectal diseases are limited. The results of a meta-analysis revealed that robotic-assisted ventral mesh rectopexy is effective and feasible in the treatment of rectal prolapse (Int J Colorectal Dis 2021;36[8]:1685-1694). A few studies have examined robotics for total proctocolectomy, and found longer operation times, shorter hospital stays and nonsignificant trends for fewer complications with robotic surgery (J Colorectal Dis 2021;36[7]:1345-1356; Dis Colon Rectum 2016;59:201-207). Studies have shown that oncologic outcomes are similar between robotic and laparoscopic total mesorectal excision (Int J Colorectal Dis 2019;34[6]:983-991). “As the footprint of robots decreases, ease of use will increase,” Dr. Uppal said.
Vivian Strong, MD, an attending surgeon at Memorial Sloan Kettering Cancer Center, and a professor of surgery at Weill Cornell Medical College, both in New York City, spoke about the role of robotics for gastric cancer. She said oncologic outcomes were equivalent with robotic and open approaches and there were advantages with a minimally invasive approach. In fact, robotic approaches have distinct advantages for selected patients, she noted. She said not all cases are appropriate for robotic approaches, and surgeons should use caution with diffuse-type tumors where margins are not well visualized and for large/bulky tumors. However, neoadjuvant chemotherapy is not a contraindication if margins can be visualized.
Adam Yopp, MD, the Occidental Chemical Chair in Cancer Research and chief of the Division of Surgical Oncology at UT Southwestern Medical Center, in Dallas, spoke about the role of robotic surgery in metastatic colorectal cancer. He said robotic-assisted partial hepatectomy for colorectal liver metastases is safe and oncologically sound in limited series. “Concomitant robotic-assisted colectomy and hepatectomy is efficacious and can avoid second surgical procedures,” he said. Robotic-assisted insertion of a hepatic artery infusion pump in high-volume robotic hepato-pancreato-biliary centers is feasible, with similar complication rates as seen in open procedures (HPB 2017;19[5]:429-435; J Surg Oncol 2016;114[3]:342-347). “Further registry trials capturing prospective data on robotic-assisted liver surgery [are] needed.”
Karim Halazun, MD, an associate professor of surgery with the liver transplantation, hepatobiliary and pancreatic surgery program at Weill Cornell Medicine, in New York City, spoke about robotic surgery for hepatocellular carcinoma (HCC). “Robotic surgery for HCC is safe. Robotic surgery for HCC is oncologically feasible and at least equivalent to open and laparoscopic surgery. There is limited literature specifically examining HCC outcomes, and therefore more data is required,” Dr. Halazun said. He noted that robotic surgery has some technical advantages over laparoscopic surgery, and better transection technology is required. He said the advantages of robotic surgery were visualization with bifocal 3D vision and Firefly; articulating instruments that improve fine hilar dissection; and easier dissection of hepatic veins due to visualization and instrumentation. Disadvantages of robotic surgery, said Dr. Halazun, included no Cavitron ultrasonic surgical aspirator, a variable setup that impedes the learning curve, and operating at a distance from the patient can induce anxiety.
According to Melissa Hogg, MD, MS, a surgeon with Northshore University HealthSystem, in Evanston, Ill., surgery has a learning curve, and this concept is revisited with each technique, including robotics. She said formal robotic training can diminish the learning curve for robotic-assisted surgery. In addition, she said, surgeons with laparoscopic experience may be able to overcome the robotic learning curve faster.
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