Mary Onysko, PharmD, BCPS; Presley Legerski and Jessica Potthoff, Targeting neuropathic pain: PharmD candidates; Michael Erlandson, MD University of Wyoming, Consider these alternatives School of Pharmacy, Laramie (Dr. Onysko, Ms. Legerski, and Ms. Potthoff); When patients with painful peripheral neuropathy fail Swedish Family Medicine, Littleton, Colo to respond to—or are unable to tolerate—standard (Dr. Erlandson) therapies, consider these lesser-known treatments. [email protected] The authors reported no potential conflict of interest relevant to this article. nticonvulsants, antidepressants, and Acetyl-L-carnitine (ALC) opioids are the most frequently pre- ALC occurs naturally in the body as L-carni- scribed medications for neuropathic tine and acetyl-carnitine esters, which are A1 pain. But some patients are unable to tol- converted to carnitines by intracellular en- erate the adverse effects of these drugs, and zymes and cell membrane transporters.2 ALC others achieve only partial pain relief. What has been studied in patients with neuropathy can you offer them? associated with human immunodeficiency instanT Combinations of prescription medica- virus (HIV), cancer, and diabetes. Potential tions are generally considered more effec- mechanisms of action include the correc- Poll tive than monotherapy for painful peripheral tion of a deficiency that may be causing the neuropathy,1 but it is unclear which combina- neuropathy (which sometimes occurs in HIV- Which of the tions are best. Alternative therapies—several positive patients13 or those taking anticon- following alterna- of which have some evidence of safety and vulsants14), a direct antioxidant effect, or an tive treatments efficacy in treating peripheral neuropathy— enhanced response to nerve growth factor.13 (if any) have you prescribed for are another option. Yet trials with alternative ALC can be given intramuscularly (IM) patients with therapies, alone or in combination with pre- or orally in doses of 2000 to 3000 mg/d. In painful peripheral scription drugs, are rarely considered. one randomized placebo-controlled trial neuropathy? In fact, physicians are often unfamiliar (N=333), patients with diabetic neuropathy with these therapies. Many are concerned received 1000 mg IM followed by an oral dose n Acetyl-L-carnitine about the absence of US Food and Drug Ad- of 2000 mg every day for a year.6 Mean pain n Alpha lipoic acid ministration approval for alternative thera- scores decreased by 39%, with 67% of those n B vitamins pies and the variability in quality control receiving ALC vs 23% of those on placebo associated with the lack of oversight, as well. showing moderate to marked improvement. n Capsaicin Making recommendations about the du- In a pooled analysis (N=1257) of 2 ran- n Gamma linolenic ration of therapy also presents a challenge domized controlled trials (RCTs), patients acid because most studies of supplements are with diabetes took 1000 mg ALC 3 times dai- n Magnesium relatively short. What’s more, alternative treat- ly or placebo for a year.7 Cohort pain scores n I have prescribed ments are rarely covered by third-party payers. improved by 40% from baseline in the ALC more than one Nonetheless, the therapies detailed in group compared with a 24% improvement for n I haven't the text and TABLE2-12 that follow are generally those in the placebo group. prescribed any well tolerated and appear to be safe. Adding of these for this them to your arsenal of therapeutic choices The bottom line ALC is well purpose z for patients with painful peripheral neuropa- tolerated, with minor adverse effects such as 470 6,7 jfponline.com thy may increase your ability to provide suc- headache and nausea reported. It should cessful treatment. not be given to patients taking acenocouma- 470 The Journal of family PracTice | AUGuST 2015 | Vol 64, no 8 Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment. rol or warfarin, however. A major interaction −1.41; P=.00001), with 0 indicating no symp- causing an elevated international normal- toms, 3 indicating severe symptoms, and a ized ratio has been found to occur when ei- maximum score of 14.64 if all symptoms were ther agent is combined with L-carnitine2 and severe and continuous. Subgroup analyses re- could theoretically occur with ALC, as well. vealed a reduction of −1.78 (95% CI, −2.45 to No other drug-drug interactions have been −1.10; P=.00001) for oral ALA and −2.81 (95% documented.2 CI, −4.16 to −1.46; P=.0001) for IV administra- tion. Doses >600 mg/d did not improve effi- cacy, but did increase adverse effects such as Alpha lipoic acid (ALA) nausea, vomiting, and dizziness. Both a fat- and a water-soluble vitamin that is In a multicenter RCT (N=460) of ALA usually obtained from the diet, ALA regener- 600 mg/d for 4 years, however, no improve- ates endogenous antioxidants like vitamins C ment in the primary endpoint (a composite and E and glutathione. It is this regenerative of neuropathy impairment scores and 7 neu- mechanism that it is believed to alleviate dia- rophysiologic tests) was found.15 Although betic neuropathy.2 ALA 600 mg/d appears to there was a statistically significant improve- be effective, although studies suggest that in- ment in symptoms of neuropathy (−0.68 with travenous (IV) use is more effective than oral ALA compared with +0.61 with placebo), the administration. change was too small to be considered clini- IMA A meta-analysis of 4 RCTs (N=653), 2 with cally significant. G ALA taken orally and 2 involving IV administra- ALA did slow the progression of neu- e : © Joe tion, is a case in point.3 The pooled standard- ropathy, however, with 29% of patients in G ized mean difference estimated from all trials the treatment group experiencing worsening orman showed a reduction in total symptom scores symptoms compared with 38% of those on of −2.26 (95% confidence interval [CI], −3.12 to placebo. There was no difference in tolerabil- JfPonline.com Vol 64, no 8 | AUGuST 2015 | The Journal of family PracTice 471 ity or discontinuation of treatment between both diabetic and alcoholic neuropathy and the 2 groups. that short-term use of higher doses of vitamin A recent observational study (N=101) B complex (25 mg B1 or 320 mg benfotiamine compared the efficacy of pregabalin, carba- + 50-720 mg B6 + 1000 mcg B12 daily) may re- mazepine, and ALA over a 21-month period.4 duce neuropathic pain.9 Although those taking pregabalin had the A randomized multicenter trial (N=214) best response rate, all 3 treatments led to sig- found that adding a supplement containing nificant improvement in the burning associ- L-methylfolate 3 mg, pyridoxal 5-phosphate ated with neuropathic pain. 35 mg, and methylcobalamin 2 mg twice dai- ALA 100 mg bid has been investigated ly to other medications (eg, pregabalin, gaba- as part of a 3-drug combination (with pre- pentin, or duloxetine) improved symptoms gabalin 75 mg bid and methylcobalamin of diabetic neuropathy.10 At 24 weeks, those 750 mcg bid) compared with monotherapy receiving the combination therapy had a 26% (pregabalin 75 mg bid) in an open random- decrease in pain symptoms compared with a ized study (N=30) for 12 weeks.16 While there 15% decrease for those on medication alone, was a trend toward improvement in pain re- with no significant adverse effects. lief, sleep interference, and nerve function in the combination therapy group, no sta- z The bottom line Overall, vita- tistically significant difference between the min B supplementation is well tolerated and IV administra- 2 groups was found. Nonetheless, more than appears to be more effective in relieving neu- tion of alpha a third (36%) had a global assessment rating ropathic pain than medication alone.9,14 But lipoic acid is of “excellent” vs one in 5 (20%) of those on larger studies are needed before its efficacy more effective pregabalin alone. in treating patients who do not have a defi- than oral ciency can be established. administration, z The bottom line Overall, ALA but patients run is well tolerated; the most common adverse the risk of an effects are nausea and skin rash. IV adminis- Capsaicin allergic reaction tration is more effective than oral administra- Capsaicin, an ingredient found in peppers, at the injection tion, but may cause nausea, headache, and works by binding to nociceptors to selec- site. an allergic reaction at the injection site.2 ALA tively stimulate afferent C fibers. This causes does have the potential for an interaction the release of substance P, a neurotransmit- with chemotherapy and thyroid hormone ter that mediates pain, leading to its deple- and may decrease the effectiveness of these tion and resulting in desensitization.2 Several therapies.2 meta-analyses and systematic reviews have found that topical capsaicin can be very effec- tive, both as an adjunctive treatment and as B vitamins monotherapy for neuropathic pain.11,17,18 The Deficiencies of vitamin B1 (thiamine), B6 concentration used in the studies was 0.075% (pyridoxine), B12 (cyanocobalamin), and capsaicin cream, applied 3 to 4 times a day for folate are known causes of neuropathy, and 6 to 12 weeks, compared with placebo creams. correcting them often improves or eliminates In all categories studied, capsaicin was either the symptoms.13 Vitamin B12 deficiency is statistically significant or trending in its favor, commonly seen in patients taking metfor- with the exception of adverse effects. min;14 these patients may benefit from sup- Capsaicin led to an improvement in daily plementation with B12 1000 mcg/d. activities and ability to sleep and a reduction Many of the B vitamins have been stud- in pain as measured with a visual analog scale ied for treatment of neuropathy, but benfo- and physician global evaluation.11,17,18 tiamine (a lipid-soluble form of thiamine) The most notable adverse effects were a is thought to be the best option because it is burning sensation on the skin and coughing better absorbed across cell membranes than and sneezing caused by inhalation of dried other B vitamins.9 A Cochrane review found cream.