Opioid Antagonists

Abstract

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Unauthorized use Bis in die, twice daily Confidence interval Continuous intravenous infusion Central nervous system Continuous subcutaneous infusion Gastrointestinal Intramuscular Intravenous Intravenous infusion Liver function test Number needed to harm Number needed to treat Nonsteroidal anti-inflammatory drug Opioid growth factor Per os, by mouth Randomized controlled trial Sublingual Subcutaneous Sustained-release Transdermal This article focuses on naloxone and naltrexone, and discusses the use of methylnaltrexone. For international educational and comparative purposes, this article also refers to some formulations not available in the USA, e.g., nalmefene. Indications: Reversal of opioid-induced respiratory depression (naloxone), acute opioid overdose (naloxone), prevention of relapse in opioid and †alcohol addiction (naloxone, naltrexone), opioid-induced constipation or post-operative ileus (methylnaltrexone, alvimopan), †pruritus caused by cholestasis1Wolfhagen F.H. Sternieri E. Hop W.C. et al.Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar or spinal opioids (naloxone, naltrexone), and possibly, chronic renal failure (naltrexone).2Peer G. Kivity S. Agami O. et al.Randomised crossover trial of naltrexone in uraemic pruritus.Lancet. 1996; 348: 1552-1554Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 3Pauli-Magnus C. Mikus G. Alscher D.M. et al.Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study.J Am Soc Nephrol. 2000; 11: 514-519PubMed Google Scholar Contraindications: these vary by drug and indication, see manufacturers' Prescribing Information for details, e.g.: Naloxone: none when used to reverse opioid-induced respiratory depression or acute opioid overdose Naltrexone: patients physically dependent on opioids (i.e., after 2 weeks of regular PO use); acute hepatitis or hepatic failure; severe renal impairment (creatinine clearance <10mL/min) Methylnaltrexone: known or suspected bowel obstruction. Naloxone, naltrexone and nalmefene (not USA) are generally thought of as pure antagonists; they have a high affinity for opioid receptors but no intrinsic activity. They reversibly block access to the opioid receptors and, if given after an opioid agonist, they displace the latter because of their higher receptor affinity.4Choi Y.S. Billings J.A. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation.J Pain Symptom Manage. 2002; 24: 71-90Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar However, the discovery that ultra-low doses of naloxone and nalmefene given postoperatively potentiate the analgesic effect of morphine and/or reduce undesirable effects (nausea and vomiting, and pruritus) means that the situation is more complex.5Gan T.J. Ginsberg B. Glass P.S. et al.Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate.Anesthesiology. 1997; 87: 1075-1081Crossref PubMed Scopus (220) Google Scholar, 6Joshi G.P. Duffy L. Chehade J. et al.Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia.Anesthesiology. 1999; 90: 1007-1011Crossref PubMed Scopus (84) Google Scholar, 7Cepeda M.S. Alvarez H. Morales O. Carr D.B. Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects.Pain. 2004; 107: 41-46Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 8Maxwell L.G. Kaufmann S.C. Bitzer S. et al.The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study.Anesth Analg. 2005; 100: 953-958Crossref PubMed Scopus (137) Google Scholar, 9Murphy J.D. Gelfand H.J. Bicket M.C. et al.Analgesic efficacy of intravenous naloxone for the treatment of postoperative pruritus: a meta-analysis.J Opioid Manag. 2011; 7: 321-327Crossref PubMed Scopus (15) Google Scholar In fact, it is over 30 years since it was shown in post-dental extraction pain that naloxone could produce either analgesia (low-dose) or hyperalgesia (high-dose).10Levine J.D. Gordon N.C. Fields H.L. Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain.Nature. 1979; 278: 740-741Crossref PubMed Scopus (245) Google Scholar Further, in the same circumstances, naloxone 400microgram neutralizes the analgesic effect of morphine 8mg IV (as expected) but more than doubles the analgesic effect of pentazocine 60mg IV.11Levine J. Gordon N. Synergism between the analgesic actions of morphine and pentazocine.Pain. 1988; 33: 369-372Abstract Full Text PDF PubMed Scopus (22) Google Scholar (Pentazocine is a partial μ and κ agonist and δ antagonist.12Hill R.G. Multiple opioid receptors and their ligands.Frontiers of Pain. 1992; 4: 1-4Google Scholar) Naltrexone appears to demonstrate similar effects.13Chindalore V.L. Craven R.A. Yu K.P. et al.Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.J Pain. 2005; 6: 392-399Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 14Largent-Milnes T.M. Guo W. Wang H.Y. Burns L.H. Vanderah T.W. Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.J Pain. 2008; 9: 700-713Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 15Hay J.L. La Vincente S.F. Somogyi A.A. Chapleo C.B. White J.M. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.Eur J Pain. 2011; 15: 293-298Crossref PubMed Scopus (14) Google Scholar In patients, ultra-low dose naltrexone potentiates the analgesic effect of methadone, oxycodone and intrathecal morphine.13Chindalore V.L. Craven R.A. Yu K.P. et al.Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.J Pain. 2005; 6: 392-399Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 16Cruciani R.A. Lussier D. Miller-Saultz D. Arbuck D.M. Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone.J Pain Symptom Manage. 2003; 25: 491-494Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 17Hamann S. Sloan P. Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a randomized, double-blind, prospective pilot study.J Opioid Manag. 2007; 3: 137-144PubMed Google Scholar These phenomena are best explained by opioid antagonists having other effects in addition to classical opioid receptor antagonism. For example, a ligand binding to an opioid receptor can trigger either an inhibitory or excitatory response, dependent on the type of G protein coupled to the receptor, either GI/GO (inhibitory) or Gs (excitatory). Typically, with an opioid agonist, the GI/GO (inhibitory) activity predominates, resulting in analgesia and other opioid effects. In such circumstances, a usual clinical dose of an opioid antagonist like naloxone will displace the opioid agonist from the receptor and thereby reverse its effects. However, the Gs excitatory response can increase in various circumstances, e.g. chronic opioid use, nerve damage.18Crain S. Shen K. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability.Pain. 2000; 84: 121-131Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar This may contribute to opioid tolerance and, when predominant, to opioid-induced hyperalgesia.19Sjøgren P. Jensen N.H. Jensen T.S. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid antagonists.Pain. 1994; 59: 313-316Abstract Full Text PDF PubMed Scopus (155) Google Scholar Ultra-low levels of naloxone interfere with the scaffolding protein (filamin A), which couples Gs to the opioid receptor and thereby inhibits the excitatory response.20Wang H.Y. Burns L.H. Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine.PLoS One. 2009; 4: e4282Crossref PubMed Scopus (49) Google Scholar Naloxone also binds to the non-opioid toll-like receptor 4 on glial cells; this interaction inhibits glial cell activation, which appears important in CNS sensitization.21Milligan E.D. Watkins L.R. Pathological and protective roles of glia in chronic pain.Nat Rev Neurosci. 2009; 10: 23-36Crossref PubMed Scopus (1085) Google Scholar, 22Ren K. Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity.Curr Opin Anaesthesiol. 2008; 21: 570-579Crossref PubMed Scopus (225) Google Scholar Glial cell activation is associated with a reduction in glutamate transporters, which impedes the synaptic clearance of this excitatory neurotransmitter. In an animal model of neuropathic pain, ultra-low dose naloxone prevented the loss of glutamate transporters and enhanced the analgesic effect of morphine.23Yang C.P. Cherng C.H. Wu C.T. et al.Intrathecal ultra-low dose naloxone enhances the antinociceptive effect of morphine by enhancing the reuptake of excitatory amino acids from the synaptic cleft in the spinal cord of partial sciatic nerve-transected rats.Anesth Analg. 2011; 113: 1490-1500Crossref PubMed Scopus (26) Google Scholar These effects of ultra-low dose naloxone at non-opioid receptor binding sites, which can improve analgesia, are lost with higher doses because of classical opioid receptor antagonism. Thus, despite the potential benefits of ultra-low dose naloxone, the inherent risk of reversal of analgesia limits the widespread clinical application of this approach and it should only be undertaken by specialists in pain or palliative medicine. In practice, if opioid-induced hyperalgesia is suspected, the first and most important step is to reduce the dose of the offending opioid.24Twycross R. Wilcock A. Toller C.S. Symptom management in advanced cancer.4th ed. palliativedrugs.com Ltd., Nottingham2009: 43-45Google Scholar Opioid antagonists are used in various clinical settings: Reversal of opioid-induced respiratory depression: The most important clinical property of naloxone is reversal of opioid-induced respiratory depression (and other opioid effects) caused by either an overdose of an opioid or an exaggerated response to conventional doses. Compared with other opioids, antagonism of buprenorphine requires higher doses of naloxone because buprenorphine also has high receptor affinity (see Dose and Use).25Foster B. Twycross R. Mihalyo M. Wilcock A. Buprenorphine.J Pain Symptom Manage. 2013; 45: 939-949Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Naloxone has been reported to be only partially effective in reversing the effects of tramadol.26Raffa R.B. Friderichs E. Reimann W. et al.Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic.J Pharmacol Exp Ther. 1992; 260: 275-285PubMed Google Scholar, 27Shipton E.A. Tramadol - present and future.Anaesth Intensive Care. 2000; 28: 363-374PubMed Google Scholar However, in a series of 11 patients with a tramadol overdose, seven had a good response to naloxone, and only one had no response.28Marquardt K.A. Alsop J.A. Albertson T.E. Tramadol exposures reported to statewide poison control system.Ann Pharmacother. 2005; 39: 1039-1044Crossref PubMed Scopus (117) Google Scholar Patients with opioid overdose may develop pulmonary edema. The exact mechanism is unclear. Because pulmonary edema has been seen both in older patients with typical doses of naloxone, e.g., 200–400microgram, and in healthy teenagers with doses as low as 40–80microgram, it has been suggested that naloxone can trigger a central neurogenic response which leads to vasoconstriction of the pulmonary vasculature followed by pulmonary edema.29Horng H.C. Ho M.T. Huang C.H. Yeh C.C. Cherng C.H. Negative pressure pulmonary edema following naloxone administration in a patient with fentanyl-induced respiratory depression.Acta Anaesthesiol Taiwan. 2010; 48: 155-157Abstract Full Text PDF PubMed Scopus (15) Google Scholar Alternatively, because pulmonary edema is almost universal in fatal opioid overdose,30Ridgway Z.A. Pountney A.J. Acute respiratory distress syndrome induced by oral methadone managed with non-invasive ventilation.Emerg Med J. 2007; 24: 681Crossref PubMed Scopus (13) Google Scholar, 31Feeney C. Ani C. Sharma N. Frohlich T. Morphine-induced cardiogenic shock.Ann Pharmacother. 2011; 45: e30Crossref PubMed Scopus (9) Google Scholar naloxone, by increasing respiratory rate and tidal volume, may simply unmask pulmonary edema which has developed secondary to severe hypoxemia and acidemia.32Clarke S.F. Dargan P.I. Jones A.L. Naloxone in opioid poisoning: walking the tightrope.Emerg Med J. 2005; 22: 612-616Crossref PubMed Scopus (138) Google Scholar Delayed-onset pulmonary edema (48h after overdose treated with naloxone) due to acute cardiomyopathy also has been reported, possibly the result of cardiac muscle damage caused by hypoxemia.33Paranthaman S.K. Khan F. Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage.Chest. 1976; 69: 117-119Crossref PubMed Scopus (29) Google Scholar Prevention of relapse in opioid addiction: Naltrexone 100mg blocks the effect of a challenge of IV diamorphine (diacetylmorphine, heroin) 25mg by 96% at 24h, and 46% at 72h.34Verebey K. The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.NIDA Res Monogr. 1981; 28: 147-158PubMed Google Scholar Thus, naltrexone is primarily used to prevent relapse in opioid addiction by blocking opioid “highs.” It also is used PO off-label to reduce the relapse rate in alcohol addiction. Naloxone is given PO either once daily or three times per week. It also is available as a long-acting depot IM injection (duration of action >1 month; authorized for use in alcohol and opioid addiction) and a SC pellet implant (not USA; duration of action weeks–months).35Volpicelli J.R. Alterman A.I. Hayashida M. O'Brien C.P. Naltrexone in the treatment of alcohol dependence.Arch Gen Psychiatry. 1992; 49: 876-880Crossref PubMed Scopus (1540) Google Scholar, 36Swift R.M. Whelihan W. Kuznetsov O. Buongiorno G. Hsuing H. Naltrexone-induced alterations in human ethanol intoxication.Am J Psychiatry. 1994; 151: 1463-1467Crossref PubMed Scopus (241) Google Scholar, 37Krupitsky E. Nunes E.V. Ling W. et al.Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial.Lancet. 2011; 377: 1506-1513Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar Opioid combination products to deter opioid abuse: In an attempt to reduce the risk of opioid abuse, PO formulations containing both a strong opioid and an opioid antagonist have been developed:•Suboxone® (buprenorphine + naloxone) given SL for opioid dependency•Embeda® (morphine + naltrexone)38Webster L.R. Brewer R. Wang C. et al.Long-term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain.J Pain Symptom Manage. 2010; 40: 734-746Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar•Targinact® (oxycodone + naloxone)39Oxycodone.in: Twycross R. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 424-429Google Scholar•OxyNal® (oxycodone + naltrexone).40Johnson F. Setnik B. Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.Pain Physician. 2011; 14: 391-406PubMed Google Scholar, 41Webster L. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations.Pain Med. 2009; 10: S124-S133Crossref PubMed Scopus (52) Google Scholar When administered PO, the opioid antagonist either remains sequestered or the amount released is insufficient to antagonize the analgesic effect of the opioid. However, if abused (e.g., the tablets crushed and administered by insufflation or IV), the opioid antagonist is then released in sufficient amounts to antagonize the opioid. Opioid-induced GI disorders: Methylnaltrexone and alvimopan are quaternary compounds which do not readily cross the blood-brain barrier and thus act as peripheral opioid antagonists. SC methylnaltrexone is authorized for use in “advanced illness” to treat opioid-induced constipation despite treatment with laxatives (see Dose and Use), and PO alvimopan is indicated for use in postoperative ileus.42McNicol E.D. Mu-opioid antagonists for opioid-induced bowel dysfunction.Cochrane Database Syst Rev. 2008; : CD006332PubMed Google Scholar, 43Becker G. Blum H.E. Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.Lancet. 2009; 373: 1198-1206Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar In the past, PO naloxone and naltrexone have been used to correct delayed gastric emptying and constipation.42McNicol E.D. Mu-opioid antagonists for opioid-induced bowel dysfunction.Cochrane Database Syst Rev. 2008; : CD006332PubMed Google Scholar However, because both are centrally acting, there is a risk of reversal of analgesia and systemic withdrawal and methylnaltrexone is now preferable. A recent systematic review and meta-analysis calculated that to prevent one patient with opioid-induced constipation failing to respond to therapy, the NNT with methylnaltrexone is 3 (95% CI 2–10) with a NNH of 14 (95% CI 9–33).44Ford A.C. Brenner D.M. Schoenfeld P.S. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis.Am J Gastroenterol. 2013; 108: 1566-1574Crossref PubMed Scopus (85) Google Scholar Because constipation in advanced disease is generally multifactorial in origin,45Larkin P.J. Sykes N.P. Centeno C. et al.European Consensus Group on Constipation in Palliative Care. The management of constipation in palliative care: clinical practice recommendations.Palliat Med. 2008; 22: 796-807Crossref PubMed Scopus (153) Google Scholar methylnaltrexone augments rather than replaces laxatives. Off-label uses of methylnaltrexone include opioid-induced constipation in postoperative46Deibert P. Xander C. Blum H.E. Becker G. Methylnaltrexone: the evidence for its use in the management of opioid-induced constipation.Core Evid. 2010; 4: 247-258PubMed Google Scholar, 47Anissian L. Schwartz H.W. Vincent K. et al.Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery.J Hosp Med. 2012; 7: 67-72Crossref PubMed Scopus (48) Google Scholar or non-surgical critical care patients48Sawh S.B. Selvaraj I.P. Danga A. et al.Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients.Mayo Clin Proc. 2012; 87: 255-259Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar and opioid-related acute colonic pseudo-obstruction.49Weinstock L.B. Chang A.C. Methylnaltrexone for treatment of acute colonic pseudo-obstruction.J Clin Gastroenterol. 2011; 45: 883-884Crossref PubMed Scopus (25) Google Scholar Methylnaltrexone also may improve other peripheral effects of opioids, e.g., urinary retention.46Deibert P. Xander C. Blum H.E. Becker G. Methylnaltrexone: the evidence for its use in the management of opioid-induced constipation.Core Evid. 2010; 4: 247-258PubMed Google Scholar Targinact® (SR oxycodone + SR naloxone) also is marketed as a product which helps reduce opioid-induced constipation. Although primarily added to deter abuse (see above), the naloxone appears to reduce the impact of the opioid on the GI tract.39Oxycodone.in: Twycross R. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 424-429Google Scholar The SR formulation helps ensure that most of the naloxone is removed by first-pass metabolism, minimizing the amount reaching the systemic circulation and the risk of reversal of analgesia. Marketing Authorization is being sought for a once daily PO formulation of a peripherally acting opioid antagonist for opioid-induced constipation (Naloxegol). Pruritus: In cholestasis, pruritus is a consequence of increased opioidergic tone caused by a raised plasma enkephalin concentration.50Davis M. Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics.Clin Pharmacokinet. 2007; 46: 825-850Crossref PubMed Scopus (48) Google Scholar, 51Metze D. Reimann S. Beissert S. Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases.J Am Acad Dermatol. 1999; 41: 533-539Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 52Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.QJM. 2002; 95: 547-552Crossref PubMed Scopus (90) Google Scholar, 53Tandon P. Rowe B.H. Vandermeer B. Bain V.G. The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.Am J Gastroenterol. 2007; 102: 1528-1536Crossref PubMed Scopus (128) Google Scholar Opioid antagonists counteract the increased tone, and thus relieve the pruritus. Naloxone by CIVI/CSCI decreases scratching activity by patients with cholestatic pruritus54Bergasa N.V. Talbot T.L. Alling D.W. et al.A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 55Bergasa N.V. Alling D.W. Talbot T.L. et al.Effects of naloxone infusions in patients with the pruritus of cholestasis.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (320) Google Scholar, 56Kumar N. Garg N. Bailey A. Opiate receptor antagonists for treatment of severe pruritus associated with advanced cholestatic liver disease.J Palliat Med. 2013; 16: 122-123Crossref PubMed Scopus (5) Google Scholar and has a place in the emergency treatment of acute exacerbations of cholestatic pruritus. PO naltrexone1Wolfhagen F.H. Sternieri E. Hop W.C. et al.Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 57Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar (or nalmefene58Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) can then be used long-term. However, opioid antagonists can precipitate an opioid withdrawal-like reaction in patients with cholestasis, including hallucinations and dysphoria.52Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.QJM. 2002; 95: 547-552Crossref PubMed Scopus (90) Google Scholar, 59Jones E. Dekker L. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar To avoid or minimize such a reaction, treatment must be started cautiously with a low dose (see Dose and Use). The use of naltrexone to relieve cholestatic jaundice may sometimes unmask or exacerbate underlying pain, necessitating discontinuation of naltrexone.60McRae C.A. Prince M.I. Hudson M. et al.Pain as a complication of use of opiate antagonists for symptom control in cholestasis.Gastroenterology. 2003; 125: 591-596Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Thus, patients with cholestatic jaundice and pruritus and severe pain should not be treated with an opioid antagonist.61Lonsdale-Eccles A.A. Carmichael A.J. Opioid antagonist for pruritus of cholestasis unmasking bony metastases.Acta Derm Venereol. 2009; 89: 90PubMed Google Scholar Instead, an alternative treatment for pruritus should be used (e.g., sertraline, rifampicin53Tandon P. Rowe B.H. Vandermeer B. Bain V.G. The efficacy and safety of bile acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus.Am J Gastroenterol. 2007; 102: 1528-1536Crossref PubMed Scopus (128) Google Scholar, 62Chan K.Y. Li C.W. Wong H. et al.Use of sertraline for antihistamine-refractory uremic pruritus in renal palliative care patients.J Palliat Med. 2013; 6: 966-970Crossref Scopus (23) Google Scholar) and the pain treated appropriately with both non-opioid and opioid analgesics. There are reports of patients with cholestatic pruritus who have responded to buprenorphine alone or in combination with ultra-low doses of naloxone.63Juby L.D. Wong V.S. Losowsky M.S. Buprenorphine and hepatic pruritus.Br J Clin Pract. 1994; 48: 331PubMed Google Scholar, 64Reddy L. Krajnik M. Zylicz Z. Transdermal buprenorphine may be effective in the treatment of pruritus in primary biliary cirrhosis.J Pain Symptom Manage. 2007; 34: 455-456Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 65Marinangeli F. Guetti C. Angeletti C. et al.Intravenous naloxone plus transdermal buprenorphine in cancer pain associated with intractable cholestatic pruritus.J Pain Symptom Manage. 2009; 38: e5-e8Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 66Zylicz Z. Stork N. Krajnik M. Severe pruritus of cholestasis in disseminated cancer: developing a rational treatment strategy. A case report.J Pain Symptom Manage. 2005; 29: 100-103Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Sometimes ultra-low doses of naloxone or naltrexone improved both the pruritus and the pain.67Jones E.A. Zylicz Z. Treatment of pruritus caused by cholestasis with opioid antagonists.J Palliat Med. 2005; 8: 1290-1294Crossref PubMed Scopus (10) Google Scholar However, there are insufficient data at present to recommend this approach. In uremic pruritus, the situation is more complex because there are several causal mechanisms, both peripheral (cutaneous) and central (neural).68Manenti L. Tansinda P. Vaglio A. Uraemic pruritus: clinical characteristics, pathophysiology and treatment.Drugs. 2009; 69: 251-263Crossref PubMed Scopus (71) Google Scholar The opioid system is involved, but in uremia there is no increase in opioidergic tone (and thus no danger of a withdrawal syndrome if an opioid antagonist is given). Instead, the ratio between μ-opioid (pruritus-inducible) and κ-opioid (pruritus-suppressive) receptors alters in favor of the former.69Kumagai H. et al.Endogenous opioid system in uraemic patients.Br J Pharmacol. 2000; 282 (Abstracts from the Joint Meeting of the Seventh World Conference on Clinical Pharmacology and IUPHAR - Division of Clinical Pharmacology and the Fourth Congress of the European Association for Clinical Pharmacology and Therapeutics)Google Scholar, 70Odou P. Azar R. Luyckx M. Brunet C. Dine T. A hypothesis for endogenous opioid peptides in uraemic pruritus: role of enkephalin.Nephrol Dial Transplant. 2001; 16: 1953-1954Crossref PubMed Scopus (12) Google Scholar This predisposes to the onset or exacerbation of pruritus. It also suggests that both κ agonists and μ antagonists could bring relief. Thus, in an RCT lasting 2–4 weeks of nalfurafine, a novel κ agonist, 36% of subjects responded (at least 50% reduction in worst itching) compared with 15% in the placebo group.71Wikström B. Gellert R. Ladefoged S.D. et al.Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies.J Am Soc Nephrol. 2005; 16: 3742-3747Crossref PubMed Scopus (242) Google Scholar Naltrexone also has been tried in this setting.72Phan N.Q. Bernhard J.D. Luger T.A. Ständer S. Antipruritic treatment with systemic u-opioid receptor antagonists; a review.J Am Acad Dermatol. 2010; 63: 680-688Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar However, RCTs have given conflicting r