Understanding and Managing Peripheral Neuropathy
Many different drugs have been used to combat the pain of peripheral neuropathy associated with HIV, diabetes, and postherpetic neuralgia (pain following a shingles episode). Unfortunately, however, there are no specific therapies effective against the other symptoms of DSPN such as numbness and tingling.
Agents from various drug classes have been tested as DSPN therapies, with mixed results. Most of these medications are aimed at managing pain, but some may actually help regenerate damaged nerves. While some trials have been done in people with HIV-related DSPN, in other cases clinicians use data from studies of neuropathy in patients with other conditions such as diabetes. People considering treatment should discuss decisions about specific regimens with their care providers. Clinicians may wish to consult with a neurologist, especially in cases of severe pain.
An initial attempt at pain control can be made with anti-inflammatory medications, including non-steroidal anti-inflammatory medications like ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), or acetaminophen (Tylenol). These agents are not typically effective against DSPN pain, however.
Several antidepressants have been used off-label for the control of neuropathic pain. Amitriptyline (Elavil) and nortriptyline (Aventyl, Pamelor) are tricyclic antidepressants that block reuptake of the neurotransmitters serotonin and norepinephrine, thereby blocking pain signaling; low doses are typically used for relief of neuropathic pain. The newer serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine (Cymbalta) and venlafaxine (Effexor) are also used to treat neuropathic pain. Duloxetine is also used to treat major depressive disorder with pain symptoms.
In a study by David Goldstein of Indiana University School of Medicine and colleagues, 457 patients with diabetic neuropathy were randomized to receive duloxetine (20, 60, or 120 mg) or placebo. Patients taking the 60-mg and 120-mg doses had significantly reduced pain severity compared with placebo recipients. There was no difference in efficacy between the two doses. A total of 49 participants discontinued the study drug due to side effects, including nausea, sleepiness, and dizziness.
Asquad Sultan of John Radcliffe Hospital in Oxford, England, and colleagues performed a systematic review of randomized trials of duloxetine for painful diabetic neuropathy and fibromyalgia pain. The six trials analyzed in the review included a total of 2,216 participants, of whom 1,510 had taken duloxetine and 706 had taken placebo. Three of the trials involved patients with diabetic neuropathy (a total of 1,020). Close to half of patients (47%) treated with duloxetine achieved 50% pain relief over baseline compared with 24% of patients treated with placebo. Studies of duloxetine for pain management of HIV-associated neuropathy are underway.
Gabapentin (Neurontin or generic equivalents) was originally developed to treat seizure disorders such as epilepsy, but it has been widely used to treat neuropathic pain. Pregabalin (Lyrica) is also used to treat seizure disorders and neuropathic pain. Both drugs are related to the neurotransmitter GABA and inhibit signal transmission to decrease pain sensation. The main side effect of gabapentin is sedation; as such, it may have helpful sleep-promoting and anti-anxiety effects for some patients.
Katrin Hahn of Charité University Hospital at Humboldt University in Berlin, Germany, and colleagues conducted a small study of gabapentin for management of HIV-associated peripheral neuropathy pain. In this trial, 15 participants were given gabapentin and 11 received placebo; 21 individuals completed the entire four-week double-blind treatment phase and two weeks of open-label treatment. There was a decrease in the median pain score (evaluated using daily pain diaries) between week 1 and week 4 in both the gabapentin and placebo groups. However, gabapentin was more effective in reducing pain; a statistically significant decrease in weekly median pain score (44.1%) was observed in the patients taking gabapentin, while the reduction in pain score in those taking placebo (29.8%) was not significant. The major limitation of this study was its small sample size.
Lamotrigine (Lamictal) is another anticonvulsant used off-label for the treatment of neuropathic pain. This drug can cause severe allergic reactions, so it should be titrated, or gradually increased, to a therapeutic dose over several weeks.
In a 2003 trial of lamotrigine for HIV-associated peripheral neuropathy, David Simpson of Mount Sinai School of Medicine and colleagues randomized 227 patients to receive lamotrigine or placebo for 11 weeks. The mean change from baseline pain score was not significantly different between the lamotrigine and placebo groups. For randomization and data analysis, participants were divided into those receiving d-drugs and those not receiving d-drugs. The group receiving d-drugs did have better improvement in pain scores over the course of the trial.
Sometimes the pain associated with neuropathy is so severe that opioid (opiate-like) analgesics such as oxycodone (OxyContin, Roxycodone), fentanyl, or morphine are required for pain control. Opioid analgesics cause sedation and constipation and have the potential for abuse, but they are effective for severe pain. Historically, many experts believed that these drugs were ineffective for nerve pain; recent research, however, suggests that opioids may be most effective for neuropathic pain when used in combination with other types of pain medication such as gabapentin.
Ian Gilron of Queen's University in Kingston, Ontario, and colleagues studied morphine, gabapentin, and a combination of the two medications for pain control in individuals with diabetic neuropathy or postherpetic neuralgia. The study was randomized and double-blind, and 41 participants completed the trial. Eligible patients had daily moderate pain for at least three months. Each treatment was given for five weeks.
The investigators found that pain scores were lower among individuals who took the gabapentin/morphine combination compared with placebo, morphine alone, or gabapentin alone. Moderate pain relief was reported by 31% of the individuals on placebo, 61% of those taking gabapentin alone, 80% of those on morphine alone, and 78% taking the morphine/gabapentin combination. Common side effects included constipation and dry mouth.
Naturally occurring in the body, acetyl-L-carnitine (ALC) is synthesized in the liver and kidneys and is crucial to normal mitochondrial function. As discussed above, abnormal mitochondrial function has been implicated in the pathogenesis of DSPN; however, it is unclear whether ALC can play a therapeutic role.
Victor Valcour of the University of Hawaii and colleagues enrolled 27 patients in an open-label single-arm study of ALC for treatment of d-drug-related peripheral neuropathy. Improvement was noted in pain, paresthesias, and numbness with ALC treatment, but no increase in epidermal nerve density or the number of mitochondrial DNA copies per cell was observed. A major limitation of the study was the lack of a placebo control group.
Andrew Hart of the Royal Free Centre for HIV Medicine at the Royal Free Hospital in London and colleagues also studied ALC in 21 HIV positive patients with peripheral neuropathy related to antiretroviral therapy and five HIV negative control subjects. Skin biopsies were performed prior to treatment and at 6- and 12-month intervals. Small sensory nerve fibers increased after six months of treatment in patients with neuropathy and 76% reported improved neuropathic pain. Again, this study included no placebo group.
Christine Herzmann, also of the Royal Free Centre for HIV Medicine, and colleagues followed up on 16 patients from the study by Hart who were available four years after the initial trial was completed. Within this group, 13 patients were still taking ALC, with an average treatment duration of 4.3 years (range 3.3 to 5.4 years), and 81% reported that their symptoms had improved "very much or moderately." The percentage of patients who required supplemental analgesics for management of neuropathy pain was 24% at 12 months and was greatly reduced to 6% at 4.3 years.
Local therapies applied directly to the painful site are an appealing treatment option due to the lower risk of drug interactions and systemic side effects. Agents that have been studied for treatment of DSPN include the topical anesthetic lidocaine and capsaicin, a component of chili peppers.
Lydia Estanislao of Mount Sinai School of Medicine and colleagues conducted a randomized, double-blind, controlled trial of 5% lidocaine gel for HIV-associated neuropathy characterized by pain or paresthesia in both feet. A total of 64 participants enrolled and were randomized to receive lidocaine or placebo gel. After two weeks, there was no difference in overall pain scores between the two groups. The investigators suggested that a dressing applied over the gel or the application of a lidocaine patch instead of a gel might provide more effective pain relief.
Capsaicin relieves neuropathic pain by desensitizing pain receptors on the skin. After application, it initially produces a burning sensation and heightened sensitivity, but then reduces sensitivity to pain. Simpson and colleagues conducted a randomized, controlled trial of a high-concentration capsaicin patch compared with a low-concentration capsaicin patch for the treatment of neuropathic pain in more than 300 HIV positive participants. Between weeks 2 and 12, there was a 22.8% reduction in pain in the high-dose capsaicin group and a 10.7% reduction in pain in the low-dose group. The most common adverse effect was local skin reactions.
Nerve growth factor. Recombinant human nerve growth factor (rhNGF) was used in a multicenter, placebo-controlled, randomized trial by Justin McArthur of Johns Hopkins University and colleagues to evaluate its efficacy as a treatment for HIV-associated peripheral neuropathy. Nearly 300 individuals were randomized to receive two different doses of nerve growth factor or placebo. After 18 weeks of randomized treatment, there was a significant difference in average and maximum pain intensity favoring rhNGF. However, there were no differences in terms of mood, analgesic use, or epidermal nerve fiber density between the groups.
Giovanni Schifitto of the University of Rochester and colleagues reported on data from the 48-week open-label phase of the rhNGF study described above. After the randomized phase, 200 of the 235 eligible patients continued taking either 0.1 or 0.3 mcg/kg of rhNGF. Neurological and quantitative sensory testing were performed at baseline and at week 48. Consistent pain improvement was observed in all groups, with the high-dose recipients demonstrating better outcomes than low-dose participants. Again, no difference in nerve fiber density was observed.
Memantine. Memantine (Namenda) is an NMDA (N-methyl-D-aspartic acid) receptor antagonist used to treat Alzheimer's disease. Although NMDA receptor antagonists theoretically should improve chronic pain, pilot studies of memantine for painful peripheral neuropathy related to diabetes have not shown improvement in neuropathic pain. Schifitto and colleagues studied memantine for treatment of HIV-associated peripheral neuropathy pain in a 16-week trial, but found no improvement in pain or paresthesia in patients taking memantine versus placebo. Only half of the 24 patients assigned to take memantine were able to tolerate the full dose.
Mexiletine. Mexiletine (Mexitil) is an oral form of lidocaine that is primarily used to suppress rapid heart rhythm. However, it also acts as an ion channel blocker to prevent pain perception and has been studied for pain control in people with diabetic neuropathy.
Carol Kemper of Santa Clara Valley Medical Center in San Jose, California, and colleagues studied mexiletine in a randomized, controlled trial that included 22 patients with HIV-associated peripheral neuropathy treated with mexiletine or placebo for six weeks. No statistically significant difference in pain score between the mexiletine and placebo groups was noted. Furthermore, the treatment was not well tolerated, with 40% of patients requiring dose reduction or discontinuation within six weeks.
Another study by Karl Kieburtz of the University of Rochester and colleagues enrolled 145 HIV positive individuals into a randomized, double-blind 10-week trial of amitriptyline, mexiletine, or placebo. They found no statistically significant improvement in pain intensity with either of the active drugs compared with placebo.
Prosaptide. Prosaptide is a drug based on human prosaposin, a protein that helps maintain and protect nerves. Scott Evans and colleagues studied Prosaptide to treat HIV-associated peripheral neuropathy. More than 200 patients were randomized to receive subcutaneous injections of different doses of Prosaptide or placebo over six weeks. The treatment was well tolerated, but produced no statistically significant difference in pain reduction compared with placebo.
Cannabis. Donald Abrams of the University of California at San Francisco and colleagues tested medicinal cannabis (marijuana) cigarettes versus similar placebo cigarettes with the cannabinoids (chemicals that give the plant its psychoactive properties) removed as a treatment for HIV-associated neuropathic pain in a five-day randomized inpatient trial.
Of the 50 participants who completed the study, the median reduction in chronic neuropathic pain (as recorded in a daily pain diary) was 34% in the cannabis group and 17% in the placebo group, a statistically significant difference. In the cannabis arm, 13 of 25 patients (52%) reported a greater than 30% decline in pain symptoms, compared with only six of 25 patients (24%) in the placebo arm. However, more participants using cannabis reported anxiety, sedation, disorientation, and confusion than those on placebo.
Erythropoietin. The hormone erythropoietin promotes red blood cell production, but may also have neuroregenerative effects. Sanjay Keswani of Johns Hopkins Hospital and colleagues studied erythropoietin using in vitro models of sensory neuropathy to see if the hormone could prevent degeneration of axons and neuronal death in nerve cells exposed to the HIV envelope protein gp120 and ddC. Erythropoietin did prevent neurotoxicity, and it likely would have a favorable side effect profile as it is a naturally occurring hormone. Currently, however, there is no clinical application of this research.
Coenzyme Q10. Also produced by the body, coenzyme Q10 (CoQ10) is essential to normal mitochondrial function. In a study presented at the 2009 Conference on Retroviruses and Opportunistic Infections, Cherry and colleagues compared CoQ10 versus ALC using in vitro testing to gauge the drugs' efficacy against toxicity due to ddI and d4T. Both ALC and CoQ10 protected against ddI toxicity; however only CoQ10 reduced toxicity from d4T. Further investigation into the clinical implications of these findings is required.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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