By Thien C Pham, BS, PharmD, Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, Agnya P Desai, BS, PharmD and Jillian L Faxon, BS, PharmD Last updated on: May 11, 2015
An estimated 34 million people live with HIV, many of whom suffer from peripheral neuropathy. Common symptoms include stabbing pain, aching, burning, numbness, and reduced sensation in the toes and hands.
Peripheral neuropathy is a common pain condition among the estimated 34 million people infected with HIV.1 The cause of neuropathy may be multifactorial. HIV itself has been associated with changes in the central and peripheral nervous systems,2 with 5.7% to 22.6% of patients with HIV experiencing peripheral neuropathy unrelated to antiretroviral treatment.3,4 Although it is not completely understood how HIV causes neuropathy, the HIV-1 envelope protein (gp120) may cause neuronal injury indirectly through Schwann cells. This may eventually induce upregulation of tumor necrosis factor-alpha, which, in turn, may result in apoptotic death of sensory neurons.5 Although HIV disease itself may cause peripheral neuropathy, comorbid conditions and medications, such as antiretroviral therapy (ART) and antituberculosis agents, also contribute to the high incidence of neuropathy in this population.3 Table 1 reviews 12 common risk factors for HIV-associated neuropathy.3
Common symptoms of peripheral neuropathy include stabbing pain, aching, burning, numbness, and reduced temperature and vibration sensation in the toes and hands.4 While there are many tools to diagnose neuropathy, few are specific to the HIV population. The AIDS Clinical Trials Group (ACTG) Brief Peripheral Neuropathy Screening Tool (BPNS) evaluates patients on a score of “11 – Always Been Normal” or “00 – Currently Absent” to 10 being the most severe based on a series of subjective and objective criteria.6
Drug-Induced Peripheral Neuropathy
Antiretroviral-Induced Peripheral Neuropathy
A vital factor in the correlation between HIV and peripheral neuropathy is the use of antiretroviral drugs. The advent of highly active antiretroviral therapy (HAART) in 1996 represented a huge breakthrough in the treatment of HIV, changing a previously fatal disease into one that is chronic but manageable.
The dideoxynucleoside analogs known to cause peripheral neuropathy are zalcitabine (withdrawn from the U.S. market in 2006), didanosine (Videx, others), and stavudine (Zerit, others).7,8 These medications inhibit neurite outgrowth and mitochondrial DNA synthesis.2 The incidence of neuropathy is related to the degree of mitrochondrial toxicity with certain nucleoside reverse transcriptase inhibitors (NRTIs), but toxicity and oxidative stress are not directly correlated.8
HIV-associated sensory polyneuropathy (HIV-SN), a painful, debilitating, peripheral neuropathy, occurs in 8% to 21% of stavudine users and 17% to 20% of didanosine users.9 In a multicenter, randomized, partially double-blind trial of 620 antiretroviral-naïve patients who were assigned to sequential 3-drug regimens with different nucleoside analogues, the development of symptomatic peripheral neuropathy was significantly more likely in patients treated with regimens containing didanosine and stavudine compared to those containing zidovudine (Retrovir, others) and lamivudine (Epivir, others) (27% vs 10%).10
Certain protease inhibitors (PIs) have been implicated in the development of peripheral neuropathy as well. However, incidences tend to be lower compared with those seen with stavudine and didanosine-based regimens.11 In a prospective, observational, multicenter study of current and past exposure to PIs, 1,159 HIV patients showed an increased risk for HIV-SN in univariate analysis.11 However, this association disappeared after the investigators adjusted for previously validated concomitant risk factors, such as dideoxynucleoside use.
Non-Antiretroviral-Induced Iatrogenic Peripheral Neuropathy
Many drug classes and specific drugs have been associated with iatrogenic neuropathies. A comprehensive overview of such therapies is beyond the scope of this review, but Table 2 lists common medications associated with drug-induced neuropathy.12,13 It is important to be aware of certain therapies that are commonly used by HIV patients that could influence the prevalence of neuropathy in this cohort of patients.
Prior infection with tuberculosis is an important component of the patient’s medical history that can contribute to peripheral neuropathy in HIV patients. Isoniazid, or isonicotinylhydrazine (INH), is a common drug used in the treatment of tuberculosis. Treatment with INH interferes with a patient’s pyridoxine (vitamin B-6) metabolism, which can ultimately cause peripheral neuropathy. Patients who are slow acetylators of INH are at an even higher risk of developing INH-induced peripheral neuropathy.14
Kaposi sarcoma is a neoplastic disorder commonly seen in patients with HIV treated with HAART. Cytotoxic chemotherapeutic regimens used to treat this include doxorubicin, paclitaxel (Abraxane, others), and vinka alkaloids, which can contribute to peripheral neuropathy. Generally, chemotherapy-induced peripheral neuropathy is sensory, cumulative, and dependent on concurrent administration of neurotoxic agents such as the taxanes (paclitaxel and docetaxel [Taxotere, Docefrez, others]) and vinka alkaloids.15 Of all vinka alkaloids, vincristine (Vincasar PFS, others) is more neurotoxic than vinblastine and vinorelbine (Navelbine, others).15 Virtually all patients receiving vincristine have some degree of neuropathy. The severity of neuropathy is dose-related.16
Taxanes are associated with peripheral neuropathy via disruption of microtubules of the mitotic spindle, which interferes with axonal transport, macrophage activation in both dorsal root ganglia and peripheral nerves, as well as microglial activation within the spinal cord.17 Paclitaxel and docetaxel are both associated with peripheral neuropathy, but neuropathy can be confused with hand-foot syndrome (acral erythema), which is also a side effect of these agents.18 Cabazitaxel (Jevtana), a semisynthetic taxane, appears to be less neurotoxic than either paclitaxel or doxetaxel.19 Neuropathies in the cancer patient, including causes and cures, has been extensively reviewed by Sasu-Tenkoramaa and Fudin.20
Study of Sensory Neuropathy
It has been estimated that 30% to 60% of patients with HIV will develop HIV-SN,2,21 which has been called distal sensory polyneuropathy, distal sensory peripheral neuropathy, and HIV-associated sensory neuropathy; one name has not been universally adopted.6
Researchers recently completed the first comprehensive sensory profile of HIV-SN in the era of combination antiretroviral treatment (cART).22 The study found that most HIV-SN patients who reported pain had a reduced ability to detect mechanical and vibration sensations, insomnia, higher plasma triglyceride levels, and higher symptom scores in depression, anxiety, and catastrophizing.22
The study, led by Tudor J.C. Phillips, from the Imperial College London’s Pain Research Group, examined 66 HIV patients from St. Stephen’s Center, Chelsea and Westminster Hospital, in London, along with 33 patients without HIV. The patients underwent an extensive clinical examination, including a structured neurological examination, a thorough quantitative sensory testing (QST) assessment, and skin biopsy. Patients then filled out a questionnaire to assess their pain symptomology, circadian rhythm disruption, quality-of-life (QoL), and psychological comorbidities.
Other data was compiled from clinical records, where available, including drug histories, nerve conduction study data, HIV virus load, CD4 counts, blood glucose, and other hematologic and biochemical parameters.
There is no gold standard for a clear case definition of HIV-SN, which, according to Phillips et al, could be hindering doctors from fully understanding this condition.23 Because of this, the researchers used a novel triumvirate case definition never used before for diagnosing HIV-SN,24 in which 2 of 3 criterion were required:
Clinical indicators from the structured neurological examination
2 or more abnormal QST findings
Intraepidermal nerve fiber density value no greater than 7.63 fibers/mm
from the skin biopsy25,26
Of the patients with HIV, 42% fit the case definition for HIV-SN. Of those, 75% reported pain, specifically in the hands and feet. This was commonly attributed to a pins and needles sensation or a feeling of numbness in approximately 60% and 75% of cases, respectively.
Concerning the Neuropathic Pain Symptom Inventory, HIV-SN patients in pain reported moderate-to-severe scores for burning pain and frequent severe scores for tingling pain. Pressure pain and pressure-evoked pain also were recorded.
These high pain scores correlated to results from various tools that reported adverse QoL in HIV-SN patients in pain. “In particular, HIV-SN patients’ physical functioning, perceptions of their physical selves, general vitality, and social functioning [were] poorer in the painful HIV-SN group compared to patients in the HIV-No SN group,” wrote Phillips et al.
HIV-SN patients were more anxious and depressed and showed “more features of cognitive impairment in response to pain compared to the control group,” the investigators noted. HIV-SN patients in pain, in particular, had notable sleep disturbances and commonly felt helpless with their pain.
The QST protocol, involving 13 thermal and mechanical stimuli on the dorsum of the patients’ feet, showed abnormalities in 85.7% of the HIV-SN group.27-29 Usually these abnormalities related to mechanical detection threshold or vibration detection threshold, with 32.14% of HIV-SN patients demonstrating a loss in both.
HIV-SN patients reported other symptoms more often than HIV-No SN patients, such as weakness in the limbs, postural hypotension, nocturnal diarrhea, and issues with urinary and erectile functions. A higher mean triglyceride plasma concentration was found in HIV-SN patients as well, lending further evidence related to how lipid dyslipidemia may play a role in the development of HIV-SN.30,31
According to study coauthor Andrew S.C. Rice, also from the Imperial College London, detailed HIV-SN sensory profiling is not only important for diagnostic purposes but also for predicting drug responses to medical treatments for HIV-SN.32
Pharmacologic Treatment
There are no consensus clinical practice guidelines for the management of chronic pain in patients with HIV. The Infectious Disease Society of America is developing clinical practice guidelines on pain management for patients with HIV and projects them to be published in Spring 2016. However, current clinical practice guidelines from organizations such as the International Association for the Study of Pain33 and the National Institute for Health and Care Excellence34 have acknowledged HIV-related neuropathy and have provided general recommendations for treatment.
For neuropathic chronic pain syndromes not due to HIV-related neuro-
pathy, we recommend and refer readers to published clinical practice guidelines for the management of neuropathic pain related to the relevant comorbidities (ie, diabetic neuropathy, cancer pain).33,34
Treatment is based largely on symptomatic presentation and usually is aimed at relieving the painful sensation. Classes of drugs used most often include anticonvulsants, antidepressants, topical analgesics, and opioids. There are no FDA-approved treatment options specifically earmarked for HIV-related and drug-induced peripheral neuropathy.
Prior to considering any treatment, an assessment of possible iatrogenic causes is in order and elimination of any offending agent should be considered, but only if the benefits of discontinuing the offending agent outweighs the risk and only if there is an therapeutically effective alternative to treat the primary disorder while reducing neuropathy risk.
Drug Interactions
Prior to considering any analgesic therapies for the HIV patient, careful consideration must be given to potential drug interactions with ART. If, for example, an antidepressant has potential to induce the enzymes responsible for metabolizing one or more ARTs, the outcome could be detrimental in that subtherapeutic ART levels may cause drug resistance—this is the reason that ART often is halted or adjusted during treatment of tuberculosis or other serious infections.35-37 This is a typical example of how the benefit of therapy for one problem must be weighed against another.
Analgesics used to treat neuropathies frequently are associated with cytochrome P450 (CYP450) drug interactions.38 Antidepressants, for example, notably are inhibitors of one or more of these enzymes and in many cases are substrates.38 Many anticonvulsants are associated with the same issues and, in fact, some, such as carbamazepine and phenytoin, are autoinducers. Moreover, many ARTs that are substrates for various CYP450 enzymes also inhibit or induce them.38 It is essential, therefore, that a comprehensive analysis be done prior to initiating any analgesic therapies in the actively treated HIV patient, particularly within these categories. It is important to note that gabapentinoids are preferred anticonvulsants in patients receiving ART because they are not metabolized by, nor do they affect, hepatic CYP enzymes.
Opioids can be beneficial to treat HIV-associated neuropathies. Unique opioids that may offer superior efficacy in this population include methadone (Dolophine, others), levorphanol, tapentadol (Nucynta), and tramadol (Ultram, others).39 Although methadone and levorphanol both offer N-methyl-D-aspartate-blocking properties and blockade of noradrenergic reuptake, methadone could be a therapeutic nightmare with respect to CYP450 drug interactions.38,40 When comparing tapentadol and tramadol, which both offer noradrenergic reuptake blockade, tramadol is a potentially problematic because it has 5 metabolites, 2 of which are active and the balance of which depend on various CYP450 enzymes to produce inactive byproducts.39 Thus, when combined with certain ART, methadone and tramadol can result in decreased efficacy or increased toxicity.
Further consideration needs to be given to patients who also are actively being treated for hepatitis C. These patients have an even greater risk of drug interactions. For example, a drug-drug interaction occurs when the p-glycoprotein inhibitor telaprevir (Incivek) is used concomitantly with methadone.41 This combination of medications could result in death.
Management of Chronic Pain In HIV-Infected Patients
Several authors have shown that patients with HIV disease and associated comorbid conditions have a higher incidence of substance abuse and medication misuse.42-44 In the authors’ opinion, it is likely that at least some of this data is skewed because it would need to be stratified for HIV causation (substance abuse disorder vs other reasons for HIV). Nevertheless, we believe that all patients requiring chronic opioid therapy should be treated with Gourley and Heit’s Universal Opioid Precautions, as suggested by various guidelines that involve consent for long-term opioid use, random urine drugs screens, ongoing assessment, etc (Table 3, page 45).45-51
Discussion
HIV-SN is a prevalent comorbidity that can significantly hinder the QoL for patients living with HIV. More importantly, this debilitating neuropathic pain condition can lead to poor medication adherence,42,52 which, in turn, can result in poor clinical outcomes (depression, substance use, opportunistic infections)53,54 that increase the likelihood of mutations and ART treatment failure.55,56 Although there are various guidelines for treating neuropathic pain generally,33,34 there is no consensus “gold standard” for diagnostically defining neuropathy; however, the recent study by Phillips et al comprehensively addresses HIV-SN via multidimensional preemptive analysis and diagnosis, and incorporates important psychosocial parameters in real time.22
From clinical and polypharmaceutical perspectives, we try to streamline therapy, such that the patient receives maximum benefit for their diagnoses (ie, depression + neuropathy = serotonin norepinephrine reuptake inhibitor). It is critically important for providers to address all medical issues (including pain) in a timely manner, modify ART therapy when clinically applicable, and initiate non-pharmacologic and pharmacologic treatment as deemed appropriate considering the patient’s drug and disease-state interactions.
As outlined by Phillips et al, certain symptoms, such as sleep disturbances, limb weakness, postural hypotension, nocturnal diarrhea, and genitourinary dysfunctions, routinely are treated without consideration of a direct correlation to unsatisfactorily controlled neuropathy. Moreover, since this study suggests a clear association between dyslipidemia and the prevalence of HIV-SN, perhaps more aggressive preventative therapy employing cholesterol-lowering agents, with particular attention to avoiding ART drug interactions, might help direct future pharmacotherapeutic interventions.
Developing evidence to predict HIV-SN prevalence by phenotype might help clinicians proactively strategize and select medications that could improve comfort, reduce comorbidities, and improve overall outcomes.
Conclusions
HIV-related neuropathy can be debilitating and can diminish the QoL in patients infected with HIV. There are no consensus clinical guidelines for diagnostically defining HIV-related neuropathy in this specific patient population. It is important for providers to understand the physiologic and pharmacologic causes of HIV neuropathy and to address reported medical issues in a timely manner, modifying treatment when clinically appropriate.
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https://www.practicalpainmanagement.com/pain/neuropathic/hiv-neuropathy/neuropathy-hiv-patients-pain-management-concerns?page=0,2
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