tiisli;iliisi<iii .liiunnil <>/ iir (1997) 58, I9G-198 CASE REPORT Naltrexone: A case report of pruritus from an antipruritic John R Sullivan and Alan Watson Department of Dermatology, Royal Newcastle Hospital, Newcastle, New South Wales, Australia CASE REPORT SUMMARY A 52-year-old woman with stage lib myeosis fungoides devel- Intense, generalized pruritus associated with mycosis oping on a background of follicular mucinosis complained of fiingoides was relieved using subcutaneous naloxone a progressively worsening itcb over the past 11 years. The itch but intensified wben changed to the new oral opioid involved her entire body from scalp to toe, including botb infil- antagonist, naltrexone. Recballcnge again led to trated plaques and normal-appearing skin. She was often cov- worsening in pruritus. This unexpected adverse effect ered with excoriations with frequent secondary infection. Tbe is surprising as naltrexone and naloxone are currently itch persisted throughout the day and was exacerbated by heat thought to work via similar opioid receptor binding. and stress. At night she woke frequently due to the itch and The worsening of tbe itch may bave been due to adap- was distressed by her bloodstained fingernails and sheets. tation in opioid receptor expression induced by pro- Medical examination including neurological and gastro- longed naloxone therapy, possibly highlighting intestinal systems, but excluding her skin, was unremarkable. differential opioid receptor affinity between naltrexone Normal investigations included: renal function, bilirubin, liver and naloxone, or may have represented an idiosyn- transaminases, bile salts, full blood count (except for lym- cratic adverse reaction. Naltrexone and naloxone have pbopenia 0.7 x lOVLj, thyroid function tests, vitamin D, been reported to reduce pruritus due to cholestasis, parathyroid hormone, calcium, magnesium, phosphate, blood uraemia, morphine epidurals, and possibly atopic der- sugar level, iron studies, urinalysis, and thoracic and matitis and urticaria. Naltrexone has the convenience abdominal computed tomography scans. Serology for HIV was of oral administration and a longer half-life. The role negaUve. Abnormal results included: elevated lactate dehydro- of the opioid system and naltrexone in pruritus is genase and 7-glutamyltranspeptidase to 1.5 times the normal reviewed. limit, which was atti'ibuted by the hepatologist to a fatty hver largely due to steroid therapy. Repeated fungal scrapings were Key words: adverse reaction, cutaneous T-cell negative. lymphoma, mycosis fungoides, naloxone. Her itch did improve to a limited extent with systemic, intra- lesional and topical eorticosteroids in combination with emollients, wet dressings and oatmeal baths. However, she INTRODUCTION suffered from mild hypertension and osteoporosis with several rib and vertebral fractures partially attributable to ber long- Unrelieved itch is a very distressing symptom and can lead to term corticosteroid therapy. Trials of several steroid-spa ring depression and even suicide or euthanasia. We report on a agents, including azathioprine, methotrexate and dapsone, patient with stage lib mycosis fungoides with intractable itch failed due to adverse drug reactions. She bad essentially no that had not been controlled with conventional therapies. Tlius improvement in symptoms with antiihistamines, altbough she a trial ofthe opioid antagonists was undertaken. NalLrexone (ound doxepin beneficial because of its sedative and calming is a pure opioid antagonist with the convenience of an oral effects. Other therapies included PLfVA phototherapy. Her itch formulation and longer half-life tban naloxone.' NalLrexone improved in two localized areas that had received spot elec- has been reported to reduce pruritus due to cholestasis,^ tron beam therapy for tumours and these areas remained free uraemia,^ morphine epidurals,* and possibly atopic dermati- of excoriations for more than 6 months. tis and urticaria.'''^ Because of the intractable itch, subcutaneous naloxone injections (0.2 mg doses) were administered at night and repeated at 3-4 hourly intervals as required. Tliis reduced the Correspondence: Dr John R Sullivan, The Skin and Cancer itch such that she was able to sleep undisturbed (for up to 4 h Foundation, 171 Bourke Si, Uarlinghiirst, (NSW 2010, Australia. at a time) for tbe first time in several years; she no longer John R Sulli\an, MB, BS(llons). Alan Watson, FACD, scratched until her sheets were stained witli blood. There were Submitted Ifi February 1997: fiicppled 2 April 1997. no other changes in her therapy or condition. After 6 weeks Pruritus and nallrexorie 197 of naloxone therapy oral nalLrexone was given. Within 30 min renal failure there may be an elevation in p-endorpbin. Thus of tiiking 50 mji of naltrexone she suffered intense generalized naltrexone (50 mg daily) has been trialled in a small, 7-day itch with subsequent uncontrollable scratching until she bled randomized, double-blind, placebo-controlled eross-over trial and she was unable tu sleep. She also described coldness in with significant symptomatic relief from pruritus.' A reduc- her arms and legs, minor paraesthesia in her fingers and toes, tion in circulating histamine, possibly due to reduced hista- and a discomfort affecting her neek. This took over a day to mine release from basophils, was also demonstrated.^ settle and recurred with subsequent self-initiated rechallenge Opioid peptides may also have a peripheral role, p-endorphin with the same dose I week later. Naloxone was recommenced and a met-enkephalin analogue eause marked enhancement but after several months of therapy she described a decline in of histamine-indueed pruritus,'' and opioids cause cutaneous its beneficial effect, which improved with an increased dose blood vessel dilatation. Met-enkephalin-like immunoreactivity (0.4 mg) and more intermittent use. has also been identified in cutaneous Merkel cells in rats.'* Opioids are also direct mast cell degranulators."' Naltrexone is chemically related to naloxone and is thought DISCUSSION to be a pure opioid competitive antagonist, with a balf-life of 3.9 h. Naltrexone is metabolized by the liver to produce simi- Pruritus arises as a consequence of afferent nerve impulses larly active metabolites. The major metabolite is 6-|3-naltrexol, transmitted via peripheral unmyelinated C fibres. These fibres which has a half-life of 12.9 h. Its pharmacological effects last are related to but distinct from those that mediate pain.'' This 24-72 h and it is largely excreted by the kidney.-"-^' Naltrexone distinction is supported by morphine's reduction in pain per- has been used to block physical dependence to heroin, mor- ception but worsening or causation of itch.^ These C fihres phine and alcohol on a trial basis in Australia and has also synapse with secondary neurones in the dorsal horn of the been used as therapy for self-injurious behaviour.""'^^ A spinal cord that send axons via the lateral spinothalamic theoretical benefit of a reduction in self-injurious behaviour, tract to the eontralateral thalanius. Tertiary neurones then possibly via dissociation of autononiic ner\ous system func- relay this information to the cortex, leading to the perception tioning,'^ is reduced scratching, leading to less skin damage, of itch.^ lichenification and subsequent perpetuation of itch. Itch is a common side effect of opioids. The literature The most common side effect of naltrexone is the opioid contains numerous reports demonstrating the reduction in witlidrawal reaction. This is minimized by performing the pruritus of different aetiologies by the opioid antagonist naloxone challenge test as outlined in the product information' naloxone.^"'"*"'^ Naltrexone has been used successfully in or the gradual introduction of naltrexone with slowly in- patients with itch due to chronic renal failure^ and epidural creasing doses, which may be important in Ihe case of morphine.* Reports in psoriasis" and urticaria and atopic der- cholestasis for the reasons described earlier. Some authors matitis,^-^ including placebo controlled trials, have achieved have thus used a small initial dose of 2 mg, which was in- variable results. There is increasing evidence for increased creased over 2-4 weeks to 50 mg to minimize opioid with- opioid activity in patients with pruritus of cholestasis.^'"''" drawal reactions." Others have started with 50 mg of Naltrexone has been used in these patients with success in naltrexone daily.'" We trialled a 50 mg daily dose because the several small trials.'"" patient had been receiving regular subcutaneous 0.2 mg Endogenous opioids have been implicated in the patho- naloxone injections for 6 weeks prior to naltrexone therapy genesis and modification of pruritus perception. Naturally being initiated. Tolerance to the antipruritic effect of naltrex- oecurring endogenous opioid peptides include the enkephalins. one has occurred with prolonged therapy, possibly due to the endorphins and the dynorphins. These interact with sev- adaptation of central opioid receptor expression.'" As the ben- eral elosely related receptors. Opioid antagonists eompetitively efieial effect was re-established following a break from ther- bind to three specific classes of opioid receptors in the CNS (i.e. apy, Carson et al. subsequently suggested 'drug holidays' of 2 p., 8 and K); there are also probably several subclasses of these days each week.'^ receptors.'' Naloxone and naltrexone bind to all these receptor Most side effects