Winter/Spring 2010
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- Introduction
- A Snapshot of the Nervous System
- Clinical Features of Peripheral Neuropathy
- Development of DSPN
- Diagnosing DSPN
- Risk Factors for DSPN
- Neuropathy Management
- DSPN Therapies
- Conclusion
- Selected Sources
Introduction
Peripheral neuropathy is the most common neurological disorder in people with HIV infection. It can be a major source of pain and discomfort and a limiting factor in antiretroviral treatment. Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the overall incidence of neurological complications of HIV -- such as HIV-associated dementia and central nervous system opportunistic infections -- has decreased; however, rates of peripheral nervous system complications remain high.
There are numerous current treatment options for peripheral
neuropathy and many new candidates under investigation. Appropriate
treatment can improve functioning and quality of life for individuals
with this common condition.
A Snapshot of the Nervous System
The nervous system enables humans to process and respond to external
and internal information. It is comprised of two major components: the
central nervous system (CNS) and the peripheral nervous system (PNS).
The CNS includes the brain and spinal
cord, which are both enclosed in bone (the skull and the vertebrae) and
surrounded by cerebrospinal fluid (CSF). The PNS consists of spinal
nerves (originating from the spinal cord) and cranial nerves
(originating from the brain), as well as ganglia, which are groups of
nerve cells located outside of the CNS. Spinal nerves have a motor nerve
root and sensory nerve root, which meet to form a single nerve.
The PNS transmits information to the CNS through afferent nerves,
which primarily pass along sensory information, and from the CNS through
efferent nerves, which primarily deliver motor commands (for example,
the command to contract a muscle). There are more than 100 billion nerve
cells in the PNS.
Functionally, the PNS is organized into two divisions: the somatic
nervous system and the autonomic nervous system. The somatic nervous
system controls receipt of sensory signals and voluntary movements. The
autonomic nervous system controls internal bodily functions that do not
require conscious effort, such as breathing and the contraction of the
heart muscle.
Nerve cells, or neurons, have a large cell body and an axon that
extends from the cell body to send signals to other nerve cells.
Branches called dendrites receive signals from other neurons. Some axons
are surrounded by cells containing myelin, a soft, fatty material that
forms a protective sheath. The myelin sheath serves as insulation so
that signals can be transmitted more quickly through the neurons.
Clinical Features of Peripheral Neuropathy
Peripheral neuropathy is one of many neurological conditions that can
affect people with HIV, and it is the most common peripheral nervous
system complication associated with HIV disease and antiretroviral
treatment. (For more on CNS manifestations, see "HIV and the Brain," BETA, Summer/Fall 2009.)
The type of peripheral neuropathy most often seen in HIV positive
people -- more specifically called distal symmetric polyneuropathy
(DSPN) -- is characterized by pain and paresthesias (abnormal sensations
such as numbness, tingling, pricking, burning, or creeping). Symptoms
typically start in the toes and progress over a period of weeks to
months, slowly moving upward to involve the lower limbs up to the knees.
The upper extremities are rarely involved at early stages. As its name
suggests, the condition typically affects both sides of the body.
Other manifestations of DSPN include allodynia (a pain response to a
normally non-painful stimulus like gentle touch), severe burning pain,
or a "pins and needles" sensation. The pain associated with DSPN can be
mild to severe and even debilitating, and may interfere with walking and
other activities of daily living.
Development of DSPN
Two types of DSPN are recognized in the context of HIV disease: DSPN
related to HIV infection itself and DSPN related to antiretroviral
therapy. In some individuals, both HIV itself and antiretroviral drugs
play a role.
HIV-related and treatment-related DSPN are impossible to distinguish
clinically; however, DSPN associated with use of the "d-drugs" or
dideoxynucleosides -- ddI (didanosine; Videx), d4T (stavudine; Zerit),
and ddC (zalcitabine; Hivid, withdrawn from the U.S. market in 2005) --
usually occurs within the first year of treatment. If an individual
tolerates early exposure to these agents, it is unlikely that
d-drug-related DSPN will develop with prolonged use.
DSPN is the result of damage to axons or loss of their protective
myelin sheaths (known as demyelination), but HIV does not directly
infect nerve cells. Instead, HIV infection leads to immune activation
and production of inflammatory chemicals called cytokines that cause
axon damage. In addition, the gp120 envelope protein of the virus causes
neuron apoptosis (cell death). Slowly, axons degenerate and are lost,
starting with the nerve cells farthest from the CNS.
DPSN caused by antiretroviral drugs is thought to be due to impaired
mitochondrial function. Mitochondria are structures within a cell that
produce energy and are involved in other crucial cell functions.
Different nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
are associated with varying degrees of mitochondrial toxicity, with ddC
causing the most damage, followed by d4T, ddI, and AZT (zidovudine;
Retrovir). The remaining drugs in this class -- 3TC (lamivudine;
Epivir), emtricitabine (Emtriva), abacavir (Ziagen), and tenofovir
(Viread) -- are less likely to interfere with mitochondrial function.
Other types of antiretroviral drugs, including non-nucleoside reverse
transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase
inhibitors, and entry inhibitors, are less likely to cause
mitochondrial toxicity.
Diagnosing DSPN
DSPN is a clinical diagnosis, based on reports of symptoms, findings
on physical exams, and ruling out other potential causes. If a patient
reports symptoms such as pain, burning, numbness, or tingling in the
feet, a neurological exam may help determine the cause of the symptoms.
A complete neurological examination includes a mental status exam
(orientation to person, place, and time), assessment of cranial nerve
function, motor function (strength in the hands and feet), sensory
function (sensation in both hands and both feet), neurovascular
examination (including pulses in the feet), reflexes, and coordination
and gait. Typical findings in people with DSPN include decreased
sensation to pain and temperature in the feet. Diminished ankle reflexes
may also be noted.
Many clinical conditions in addition to
HIV can cause DSPN, including diabetes, alcoholism, thyroid disease,
syphilis, hepatitis C, kidney disease, and vitamin B12 deficiency. A
careful clinical history and laboratory testing are used to rule out
these conditions. Use of neurotoxic drugs can also suggest a diagnosis
of DSPN.If an individual has atypical symptoms -- for example, an asymmetric distribution of numbness or pain, or weakness as the presenting symptom rather than sensory impairment -- additional testing may be required to reach a diagnosis.
Nerve conduction velocity (NCV) testing or electromyography (EMG) can be used to evaluate neurological symptoms. NCV checks the speed of signals transmitted through nerves using electrodes placed on the surface of the skin. NCV only detects damage to large nerves, so it may not detect DSPN, which predominantly affects small nerves.
EMG uses a thin needle electrode placed into muscle tissue to monitor electrical activity and detect whether the muscle has a normal ability to respond to electrical stimuli from nerves. In people with DSPN, EMG testing can occasionally show evidence of denervation (loss of nerve supply) in the distal (farther from the hips and shoulders) muscles of the limbs, such as those in the calves and forearms. EMG can also help distinguish DSPN from related neurological problems such as those associated with aging.
Another type of testing frequently used in DSPN research, but less frequently in clinical care, is quantitative sensory testing, a non-invasive method used to assess the ability of nerves to respond to vibration and temperature. This test provides useful information about the extent of neuropathy and whether a patient is responding to treatment.
Skin biopsy with analysis of epidermal nerve fiber density is also frequently used in DSPN research. Small skin samples are usually taken from the thigh, calf, and/or foot. Low nerve fiber density (<11 fibers/mm) in the skin has been shown to correlate with increasing severity of neuropathy symptoms and elevated risk of neuropathy progression.
As mentioned above, DSPN is a clinical diagnosis, and additional testing is not required unless the diagnosis is in question because of unusual symptoms or physical findings. Other types of neuropathy may be seen in people with HIV, but these are considerably less common than DSPN.
Inflammatory demyelinating polyneuropathy (known as Guillain-Barré syndrome in its acute form) is marked by progressive weakness of the extremities and poor reflexes at all sites. Progressive polyradiculopathy (damage to nerve roots near the spine) can be caused by the opportunistic infection cytomegalovirus or herpes simplex virus; this mostly occurs in people with CD4 counts below 200 cells/mm3. Polyradiculopathy is characterized by weakness and numbness in the feet, bowel incontinence, bladder retention (difficulty passing urine), and saddle anesthesia (lack of feeling in the perineum, the region between the anus and the scrotum or vagina).
Mononeuropathy (damage to a single nerve or nerves in a single area) may be caused by acute HIV infection or by nerve compression. Signs may include foot drop, facial droop, or paralysis of the diaphragm (the sheet of muscle in the chest used for breathing). Mononeuropathies are uncommon in people with HIV and are easily distinguishable from DSPN. Today, many cases of mononeuropathy are due to repetitive stress injuries such as carpal tunnel syndrome.
Risk Factors for DSPN
The prevalence of DSPN ranges from 9% to about 60% in the various cohorts of HIV positive individuals that have been studied. Risk factors for DSPN both before and after the introduction of HAART have been examined.In the pre-HAART era, DSPN was associated with advanced HIV disease and severe immunosuppression. Risk factors currently associated with DSPN include older age, lower nadir (lowest-ever) CD4 cell count (especially if less than 50 cells/mm3), nutritional deficiencies, diabetes, concurrent use of neurotoxic drugs, heavy alcohol use, and low epidermal nerve fiber density. Most recent studies indicate that aging is a pivotal factor, and duration of HIV infection may also play a role.
A substudy of neurological outcomes in the Multicenter AIDS Cohort Study was initiated in 1986 to observe the incidence of HIV-associated neurocognitive impairment and sensory neuropathy. Looking at more than 1,600 men who have sex with men over the ten-year follow-up period, 213 cases of sensory neuropathy were identified, of which 66 were HIV-associated, 43 were due to drug toxicity, and 104 were mixed. Although neuropathy was associated with high viral load (above 30,000 copies/mL) and low CD4 count (less than 200 cells/mm3), after the data were adjusted for prior AIDS-defining illness or antiretroviral use, the association was no longer statistically significant.
Alejandro Arenas-Pinto of the Centre for Sexual Health & HIV Research in London and colleagues reported on data from the Delta trial, a randomized, double-blind trial conducted from 1992 to 1995 comparing NRTI monotherapy and dual-therapy regimens. The original study involved three therapeutic arms: AZT, AZT plus ddI, and AZT plus ddC. The substudy focused on time from treatment initiation to onset of peripheral neuropathy. The researchers examined whether peripheral neuropathy was associated with cumulative NRTI use or whether a brief exposure was sufficient to develop the condition.
The analysis included data from 3,195 patients; 177 new cases of peripheral neuropathy developed in the cohort. DSPN incidence was highest in the AZT/ddC group, with 6.2 cases per 100 person-years (PY), versus 3.0 cases per 100 PY in the AZT monotherapy group and 2.2 cases per 100 PY in the AZT/ddI group. The incidence of DSPN rose in the 90 days after participants were randomized to these treatment groups and started therapy, then decreased over time, suggesting that cumulative exposure to NRTIs does not increase the likelihood of developing peripheral neuropathy. Lower CD4 count and older age, but not sex, were associated with developing DSPN. The study authors hypothesized that there may be an underlying predisposition to DSPN which leads certain individuals to develop the condition within the first 90 days of exposure to a neurotoxic agent.
In a study by Kenneth Lichtenstein of the University of Colorado Health Sciences Center and colleagues, nearly 2,000 treatment-experienced participants from the HIV Outpatient Study (HOPS) cohort were followed to observe the development of peripheral neuropathy. The investigators found that older age, lower CD4 count, and higher viral load were associated with development of DSPN. The use of d4T slightly increased the risk of DSPN; however, earlier initiation of HAART -- even a regimen including d4T -- provided more protection against DSPN than withholding combination antiretroviral therapy. After six to twelve months of therapy, the incidence of DSPN reached a plateau.
Further analysis of the HOPS data revealed an increase in DSPN from 1992 to 1995 following introduction of the d-drugs, then a decrease starting with the introduction of PI- and NNRTI-based HAART in 1996. A lower nadir CD4 count was associated with higher incidence of DSPN. In the HAART era, risk factors for peripheral neuropathy included age greater than 40 years, diabetes, nadir CD4 count less than 50 cells/mm3, and viral load greater than 10,000 copies/mL.
Another HAART-era study by Catherine Cherry of Monash University in Melbourne, Australia, and colleagues enrolled 147 HIV positive adults, 76 from Johns Hopkins University in Baltimore, and 71 from Monash. The Melbourne group was enrolled first and subsequently the Baltimore group was matched according to rates of prior exposure to d4T and ddI.
At enrollment, study participants were divided into three groups: neuropathy-free, asymptomatic neuropathy (with physical signs on examination but no symptoms), and symptomatic neuropathy (with both signs and symptoms). At baseline, only 37% were characterized as neuropathy-free. Most patients had prior exposure to d-drugs (79% in the Johns Hopkins group; 83% in the Monash group). Symptomatic neuropathy was associated with history of exposure to ddI or d4T and age greater than 40 years. Race, sex, viral load, hepatitis C coinfection, and levels of lactic acid, hemoglobin A1c (a measure of glucose control over three months), and vitamin B12 were not associated with neuropathy in this study.
Investigators have tried to determine whether protease inhibitors, like the d-drugs, contribute to the development of DSPN. Jacqueline Petterson of the University of Calgary and colleagues studied a sample of HIV positive individuals with neurological disorders, dividing them into two groups: those with some form of neuropathy or neurological disorder (neurocognitive impairment, back pain, headache, etc.) and those without. Of the 221 patients studied, 101 had neuropathy; of those, 64 (29%) had DSPN related to HIV and 37 (17%) had DSPN related to antiretroviral therapy. Further analysis revealed that d-drugs and certain PIs -- namely ritonavir (Norvir), saquinavir (Invirase), and indinavir (Crixivan) -- were associated with DSPN.
However, a subsequent study by Ronald Ellis of the University of California at San Diego and colleagues yielded conflicting results. This group analyzed data from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, a large, multicenter prospective study to evaluate the neurological effects of HAART. DSPN was present in 58% of a sub-sample of participants who had been assessed for peripheral neuropathy at baseline, and 58% of these (34% of all participants) had symptoms. Patients with DSPN were older, had a lower median nadir CD4 count, and were more likely to have had an AIDS diagnosis. They were also more likely to be taking antiretroviral therapy and therefore had lower viral loads.
Participants were divided into groups based on antiretroviral use, with special attention to PI exposure. After the analysis was adjusted to account for age, CD4 nadir, viral load, and duration of antiretroviral treatment, there was no difference in rates of DPSN between the groups based on PI use. In terms of individual PIs, once adjusted for other risk factors, only amprenavir (Agenerase; now discontinued) and lopinavir/ritonavir (Kaletra) were associated with DSPN. The authors concluded that the independent risk of DSPN attributable to PIs is likely very small and should not preclude their use.
Susan Morgello of Mount Sinai School of Medicine and colleagues published data from the Manhattan HIV Brain Bank, which enrolled 187 patients between January 1999 and June 2002. Baseline neurological exams were performed and detailed clinical and psychiatric and substance use histories were obtained. The researchers found that 53% of the participants had DSPN at baseline, of whom almost one third were asymptomatic. Interestingly, opiate and sedative abuse or dependency was associated with asymptomatic DSPN.
To determine whether there is a genetic predisposition to develop DSPN, Todd Hulgan of Vanderbilt University School of Medicine and colleagues evaluated participants in ACTG 384, a study of HIV positive patients taking ddI/d4T or AZT/3TC with efavirenz (Sustiva), nelfinavir (Viracept), or both. DNA samples were available from 526 participants. Among these patients, 17 (3.2%) had peripheral neuropathy at baseline and were excluded from this analysis. Of the 509 remaining participants, 147 developed DSPN; within this group, a majority (108 patients; 73%) had been randomized to the ddI/d4T arm. Patients who developed DSPN were older and had higher baseline viral load and lower baseline CD4 count.
Geneticists use mitochondrial haplogroups to define populations with similar genetic backgrounds. The Caucasian participants from ACTG 384 were divided into the European haplogroups, and haplogroup T was identified more frequently in patients with peripheral neuropathy. In a multivariable regression analysis examining predictors of neuropathy, variables with a significant association included ddI/d4T use, older age, and haplogroup T. Between 10% and 15% of individuals of European descent belong to mitochondrial haplogroup T.
Jeffrey Canter of Vanderbilt University School of Medicine and colleagues expanded the haplogroup work from ACTG 384; they presented their results at the 2009 Conference on Retroviruses and Opportunistic Infections. Among 156 African-American ACTG 384 participants without baseline peripheral neuropathy, 51 developed DSPN. Patients with haplogroup L1c were more likely to develop DSPN than those of other sub-groups. Older age, ddI/d4T use, and haplogroup L1c were independent predictors of DSPN.
Finally, Beau Ances of Washington University School of Medicine and colleagues examined the relationship between metabolic syndrome and HIV-associated DSPN in 1,556 participants in the CHARTER study followed from 2003 through 2007. Metabolic syndrome is characterized by insulin resistance, high blood pressure, central obesity, decreased HDL ("good") cholesterol, and elevated triglycerides. In this analysis, 130 participants were found to have DSPN; however, metabolic syndrome and DSPN were not correlated. Patients with elevated triglycerides and diabetes had an increased risk of peripheral neuropathy, just as in the general population.
Neuropathy Management
The first step in DSPN management is optimal control of HIV disease with antiretroviral therapy. Although data are not entirely consistent, many studies have shown that higher viral load and lower current or nadir CD4 count are associated with peripheral neuropathy. HAART minimizes this risk by suppressing HIV replication and allowing CD4 cells to recover.The next step is to discontinue any potentially neurotoxic agents, if possible. As discussed above, the antiretroviral agents most often associated with peripheral neuropathy are the d-drugs. Use of multiple d-drugs is particularly likely to cause problems. The ddI/d4T combination was once widely used as an NRTI "backbone" but fell out of favor due to increasing evidence of mitochondrial toxicity. U.S. treatment guidelines no longer consider ddI or d4T to be components of "preferred" or "alternative" regimens, but they are still commonly used in resource-limited settings (see table below).
Today, d-drugs are seldom used by people starting HIV therapy for the first time in high-income countries, and many treatment-experienced patients have switched to NRTIs less likely to cause neuropathy (3TC, emtricitabine, abacavir, and tenofovir). Studies indicate that neuropathy improves after stopping these drugs, but the change may be slow and incomplete.
In addition to antiretrovirals, there are many other potentially neurotoxic agents used in HIV care, including dapsone (sometimes used for Pneumocystis pneumonia prophylaxis), thalidomide (infrequently used to treat aphthous ulcers, or canker sores), isoniazid and ethambutol (tuberculosis drugs), and certain cancer chemotherapy agents (for example, vincristine).
Numbness due to DSPN may contribute to problems with walking, leading to falls and other injuries. Physical or occupational therapy may be helpful, as well as practical measures such as removing throw rugs and other fall hazards.
DSPN Therapies
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.
Anti-Inflammatories
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.
Antidepressants
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.
Anticonvulsants
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.
Opioids
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.
Acetyl-L-Carnitine
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 Treatments
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.
Other Therapies
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.
Conclusion
DSPN remains a pervasive problem for people with HIV in the HAART
era. The risk of developing peripheral neuropathy can be minimized by
detecting HIV disease early to allow for appropriate monitoring of viral
load and immune status, as well as timely initiation of antiretroviral
treatment. Working with a knowledgeable care provider, HIV patients
today can construct effective modern combination regimens that avoid
neurotoxic drugs.
Further research is needed to develop additional options for
neuropathy prevention and treatment. However, when DSPN does occur, it
can be managed in an individualized manner using a wide range of agents
for pain control. Researchers are also working on future therapies that
may enable nerve regeneration and reversal of existing damage.
Anne Monroe, M.D., M.S.P.H., is a board-certified internist
providing clinical care to HIV positive individuals. Her research
interests include the prevention and treatment of sexually transmitted
infections and HIV-related illnesses and conditions.
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