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HIV-Related Pain Syndromes

Egle Bavry, M.D.
Department of Anesthesiology
University of Florida and North Florida/South Georgia VA

Robert W. Hurley, M.D., Ph.D.
Department of Anesthesiology, Neurology, Psychiatry, Orthopedics and Rehabilitation, and Neurosurgery
University of Florida

Introduction - TOP

With the development and widespread use of highly active antiretroviral therapy (HAART) and the resulting decrease in opportunistic infections of the central nervous system, polyneuropathy has become the most prevalent neurological complication associated with human immunodeficiency virus (HIV) infection.1 Although symptomatic neuropathy occurs in 10 to 35% of those seropositive for HIV, pathologic abnormalities exist in almost all of those with end-stage AIDS.1, 2 There are numerous types of the HIV-associated neuropathy classified by onset, putative etiology, pathology of nerve damage, and motor or sensory involvement (please see Keswani3 for review). The sensory neuropathies associated with HIV (HIV-SN) include distal sensory polyneuropathy (DSP) due to the viral infection and antiretroviral toxic neuropathy (ATN) due to the medical treatment of the viral illness. DSP represents the more common of the two disorders.

Although these HIV-SNs may represent two distinct entities,4 the clinical syndrome, and pathophysiologic manifestation of the two disorders are practically indistinguishable. The time course of the illness and temporal relation to the commencement of anti-retroviral therapy represents the primary differentiating characteristic. The onset of DSP can occur in either the subacute or chronic phases, or following the development of an AIDS-defining illness. The clinical manifestation of ATN can appear within the first week to six months of the initiation of antiretroviral therapy and may subside after its cessation.

Pathophysiology - TOP

Distal Sensory Polyneuropathy

The pathogenesis of DSP axonal or DRG loss has not been fully elucidated. It may represent both direct peripheral nerve damage by the virus or the indirect consequences of the infection resulting in an aberrant inflammatory response from the activation of cytokines and other inflammatory mediators. Likewise, the pathogenesis of pain in DSP is not fully explained by the direct action of the virus or the multifocal inflammatory response. Gp120, the viral coat protein of HIV, has been found to produce pain in rats when administered epineurally to the sciatic nerve8 and intradermally into the paw.9 It also directly stimulates small neurons of the DRG9 suggesting HIV can directly activate peripheral nerves and result in pain. The indirect causes of DSP pain are thought to be mediated by inflammatory injury.3 These can be divided into peripheral and central mechanisms. The peripheral hypothesis is that after the injury of nerve fibers the pain results from spontaneous activity of uninjured adjacent pain transmitting C fibers. Inflammatory mediators released by macrophages may further sensitize these fibers. The central hypothesis involves alteration in ion channels in the DRG combined with changes in the spinal cord dorsal horn resulting in “central sensitization”.

Antiretroviral Toxic Neuropathy

The pathogenesis of ATN is directly related to the use of nucleoside reverse transcriptase inhibitors (NRTIs). In this last decade the incidence of HIV-SN has increased with the introduction and increased use of NRTIs and protease inhibitors.10 The NRTIs (zalcitabine, ddC; didanosine, ddI; stavudine, d4T) are known to be neurotoxic and in phase I clinical trials of ddC, ATN was found to be a dose and duration related phenomena.11 ddI and d4T are less neurotoxic when administered alone, however the combination of the two along with other HIV medications increases the risk of developing ATN considerably.12 NRTIs toxicity is thought to be mediated by mitochondrial dysfunction resulting in lactic acidosis, mitochondrial DNA depletion, and cellular death. Unfortunately the damage is not always reversible. Cessation of NRTIs therapy results in improvement of symptoms in only one-third of patients.

Clinical Features - TOP

The clinical features of HIV-SN are dominated by painful dysesthesia, allodynia (a stimulus previous not found to be noxious is perceived as painful) and hyperalgesia (a lower pain threshold). Onset is often gradual and most commonly beginning with bilateral lower extremity involvement. The neuropathy progresses in a length dependent fashion with a worsening gradient of disease from distal structures to those more proximal. The dysesthesias commonly first involve the soles of the feet and progress proximally; when the symptoms encompass the dermatomes of the knee the patient will often report finger involvement. The first symptoms noted are often numbness or burning sensation following a diurnal cycle with the pain worse at night. Shortly thereafter, patients will report allodynia and hyperalgesia of the involved structures. As a result, wearing shoes and walking become painful and the patient’s gait becomes antalgic.

There is minimal subjective or objective motor involvement and is generally limited to the intrinsic muscles of the foot. Physical examination shows a diminution or loss of ankle reflexes in addition to the sensory findings.

Diagnostic Examination - TOP

Serum and cerebrospinal fluid laboratory examinations generally do not show any abnormalities. Electrophysiological studies, although primarily testing large myelinated fibers, show an axonal, length-dependent, sensory polyneuropathy. Skin biopsies of the distal lower extremity show decreased intraepidermal nerve density indicative of loss of small, unmyelinated fibers5, 6 and later Wallerian degeneration of myelinated fibers similar to autonomic neuropathy of diabetes mellitus. Dorsal root ganglion (DRG) neuronal loss has been reported, although the reduction is more modest than of the distal axon loss.7

Treatment - TOP

Symptom Management

Treatment of HIV-SN is symptomatic as there are no therapies proven to restore the underlying pathology to the pre-injured state. Treatment begins with optimization of the patient’s metabolic and nutritional status and exclusion of alternate explanations for the neurologic symptoms. In patients with presumed ATN, cessation or dose reduction of NRTIs can be beneficial in a portion of patients. Unfortunately, the symptoms of ATN can worsen for up to 2 months after cessation of therapy. A number of studies have been performed to investigate the efficacy of some therapies in the control of neuropathic pain symptoms of HIV-SN. Unfortunately, therapies commonly administered to patients with non HIV-SN related neuropathic pain including amitriptyline, mexiletine, memantine, topical lidocaine or low-dose topical capsaicin did not show any benefit in double blind, randomized, placebo-controlled trials (RCTs).13, 14, 15, 16 Less traditional therapies such as acupuncture were also of no significant benefit.17

One randomized, double-blind, placebo-controlled trial of nimodipine (60 mg orally five times daily and 30 mg orally three times daily) taken concurrently with antiretroviral medications, showed a trend towards improvement or stabilization in neuropathy when compared with placebo.18 In two RCTs, lamotrigine (300mg/day) was found to significantly reduce pain in DSP but not ATN19 and in a larger trial this drug was found to be effective in ATN as well.20

The evidence for the effectiveness of gabapentin in the treatment of pain associated with HIV-SN, which had previously been derived from case-reports and open label trials,21, 22 has now been supported by a properly conducted RCT.23 In this study, after 4 weeks of gabapentin therapy (1200 – 3600 mg/day) pain and sleep interference scores were significantly lower in the gabapentin group as compared to placebo. Adverse events were minimal; the only statistically significant side effect was increased somnolence.

Medicinal cannabis has been recently reported in a randomized crossover trial to provide benefit in HIV induced DSP pain.24 In this study of modest size, 46% of subjects who smoked cannabis 4 times a day for 5 consecutive days experienced a reduction in pain intensity of greater than 30%. Although few negative side effects were noted, it is unlikely that the dysphoria associated with inhaled cannabis can be fully separated from its analgesic properties.

High dose topical capsaicin (8%) applied once to an affected extremity was found to be effective in reducing HIV-SN pain.25 Thirty-one percent of patients treated with 8% capsaicin for 30 min experienced a >30% reduction in pain for the 12 week evaluation period. Side effects included a short-term increase in pain and redness at the site of capsaicin application. The erythema and edema resolved after removal of the capsaicin cream and the increase in pain was managed with local cooling and short-acting opioids (a total of 5 mg of oral oxycodone more than in control subjects).

Prescribing Recommendations for Symptom Management

Medication Class

Starting Dose

Titration

Maximum Daily Dosage

Duration of Adequate
Trial

Major Side Effects

Other Benefits

Calcium Channel Ligand

Gabapentin

100-300 mg QD-TID

Increase
by
100-300 mg TID every 3-7 days
until pain relief

3600 mg

4-8 weeks
with
>2 wks at maximum
dose

Sedation, dizziness, peripheral edema
(weight gain)

Improvement in sleep

Nimodipine   90 mg  
Sodium Channel Ligands

Lamotrigine

25 mg QD

Increase by 25 mg every week until pain relief

300 mg

 

Stevens-Johnson syndrome, dizziness, headache, blurred vision

 
Mexiletine   No benefit  
Topical Lidocaine   No benefit  
Anti-Depressant

Amitriptyline

25 mg QHS

increase by 25 mg
every 3-7 days until pain relief

150 mg

6-8 wks with
>2 wks at maximum
dose

Sedation,
dry mouth, blurred
vision,
urinary retention

Improvement of depression and sleep

Other

Topical Capsaicin

8% cream once to affected
area

None

Once, repeat every
four months

No trial

Temporary pain, edema, erythema

 

Cannabis

INH QID

None

QID

No trial

Dysphoria, increased appetite

 

Restorative Treatment

Although the primary treatment for HIV-SN has been management of the pain symptoms, attempts have been also been made to reverse or treat the etiology of the painful neuropathy. These have included less traditional therapies including peptide T treatment that were without benefit.19 An eighteen week RCT found treatment with nerve growth factor (NGF) (0.1 to 0.3 mg/kg) produced a modest but significant improvement in pain in patients with HIV-SN.26

Summary - TOP

HIV-SN is now the most prevalent neurologic consequence of HIV infection. Although the advent of NRTI has produced an enormous morbidity and mortality benefit for those suffering with HIV, it has also increased the incidence of HIV-SN directly and indirectly. The incidence and prevalence of HIV-SN are substantial and as other morbidities associated with HIV infection are lessened by aggressive pharmacotherapy, the need for effective treatment of this neuropathic pain becomes more imperative.

References - TOP
  1. Verma A. Epidemiology and clinical features of HIV-1 associated neuropathies. J Peripher Nerv Syst 2001;6:8-13
  2. Schifitto G, McDermott MP, McArthur JC, Marder K, Sacktor N, Epstein L, Kieburtz K. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology 2002;58:1764-8
  3. Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated sensory neuropathies. Aids 2002;16:2105-17
  4. Luciano CA, Pardo CA, McArthur JC. Recent developments in the HIV neuropathies. Curr Opin Neurol 2003;16:403-9
  5. McCarthy BG, Hsieh ST, Stocks A, Hauer P, Macko C, Cornblath DR, Griffin JW, McArthur JC. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 1995;45:1848-55
  6. Polydefkis M, Yiannoutsos CT, Cohen BA, Hollander H, Schifitto G, Clifford DB, Simpson DM, Katzenstein D, Shriver S, Hauer P, Brown A, Haidich AB, Moo L, McArthur JC. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 2002;58:115-9
  7. Bradley WG, Shapshak P, Delgado S, Nagano I, Stewart R, Rocha B. Morphometric analysis of the peripheral neuropathy of AIDS. Muscle Nerve 1998;21:1188-95
  8. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol 2001;116:29-39
  9. Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 2001;21:5027-35
  10. Pettersen JA, Jones G, Worthington C, Krentz HB, Keppler OT, Hoke A, Gill MJ, Power C. Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol 2006;59:816-24
  11. Berger AR, Arezzo JC, Schaumburg HH, Skowron G, Merigan T, Bozzette S, Richman D, Soo W. 2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology 1993;43:358-62
  12. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. Aids 2000;14:273-8
  13. Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, Marra CM, McKendall R, Singer E, Dal Pan GJ, Clifford DB, Tucker T, Cohen B. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998;51:1682-8
  14. Paice JA, Ferrans CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symptom Manage 2000;19:45-52
  15. Schifitto G, Yiannoutsos CT, Simpson DM, Marra CM, Singer EJ, Kolson DL, Nath A, Berger JR, Navia B. A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy. J Neurovirol 2006;12:328-31
  16. Estanislao L, Carter K, McArthur J, Olney R, Simpson D. A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 2004;37:1584-6
  17. Shlay JC, Chaloner K, Max MB, Flaws B, Reichelderfer P, Wentworth D, Hillman S, Brizz B, Cohn DL. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA 1998;280:1590-5
  18. Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA. A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 1998;51:221-8
  19. Simpson DM, Dorfman D, Olney RK, McKinley G, Dobkin J, So Y, Berger J, Ferdon MB, Friedman B. Peptide T in the treatment of painful distal neuropathy associated with AIDS: results of a placebo-controlled trial. The Peptide T Neuropathy Study Group. Neurology 1996;47:1254-9
  20. Simpson DM, McArthur JC, Olney R, Clifford D, So Y, Ross D, Baird BJ, Barrett P, Hammer AE. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003;60:1508-14
  21. La Spina I, Porazzi D, Maggiolo F, Bottura P, Suter F. Gabapentin in painful HIV-related neuropathy: a report of 19 patients, preliminary observations. Eur J Neurol 2001;8:71-5
  22. Newshan G. HIV neuropathy treated with gabapentin. Aids 1998;12:219-21
  23. Hahn K, Arendt G, Braun JS, von Giesen HJ, Husstedt IW, Maschke M, Straube ME, Schielke E. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol 2004;251:1260-6
  24. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009;34:672-80
  25. Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008;70:2305-13
  26. McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, Marra C, Rubin M, Cohen BA, Tucker T, Navia BA, Schifitto G, Katzenstein D, Rask C, Zaborski L, Smith ME, Shriver S, Millar L, Clifford DB, Karalnik IJ. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 2000;54:1080-8

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