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Opioid Antagonists

      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] ).

      Abbreviations

      Unauthorized use
      b.i.d.
      Bis in die, twice daily
      CI
      Confidence interval
      CIVI
      Continuous intravenous infusion
      CNS
      Central nervous system
      CSCI
      Continuous subcutaneous infusion
      GI
      Gastrointestinal
      IM
      Intramuscular
      IV
      Intravenous
      IVI
      Intravenous infusion
      LFT
      Liver function test
      NNH
      Number needed to harm
      NNT
      Number needed to treat
      NSAID
      Nonsteroidal anti-inflammatory drug
      OGF
      Opioid growth factor
      PO
      Per os, by mouth
      RCT
      Randomized controlled trial
      SL
      Sublingual
      SC
      Subcutaneous
      SR
      Sustained-release
      TD
      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 cholestasis
      • Wolfhagen F.H.
      • Sternieri E.
      • Hop W.C.
      • et al.
      Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study.
      or spinal opioids (naloxone, naltrexone), and possibly, chronic renal failure (naltrexone).
      • Peer G.
      • Kivity S.
      • Agami O.
      • et al.
      Randomised crossover trial of naltrexone in uraemic pruritus.
      • Pauli-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.
      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.

      Pharmacology

      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.
      • Choi Y.S.
      • Billings J.A.
      Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation.
      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.
      • Gan T.J.
      • Ginsberg B.
      • Glass P.S.
      • et al.
      Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate.
      • Joshi 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.
      • Cepeda 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.
      • Maxwell 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.
      • Murphy J.D.
      • Gelfand H.J.
      • Bicket M.C.
      • et al.
      Analgesic efficacy of intravenous naloxone for the treatment of postoperative pruritus: a meta-analysis.
      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).
      • Levine J.D.
      • Gordon N.C.
      • Fields H.L.
      Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain.
      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.
      • Levine J.
      • Gordon N.
      Synergism between the analgesic actions of morphine and pentazocine.
      (Pentazocine is a partial μ and κ agonist and δ antagonist.
      • Hill R.G.
      Multiple opioid receptors and their ligands.
      ) Naltrexone appears to demonstrate similar effects.
      • Chindalore 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.
      • Largent-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.
      • Hay 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.
      In patients, ultra-low dose naltrexone potentiates the analgesic effect of methadone, oxycodone and intrathecal morphine.
      • Chindalore 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.
      • Cruciani R.A.
      • Lussier D.
      • Miller-Saultz D.
      • Arbuck D.M.
      Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone.
      • Hamann S.
      • Sloan P.
      Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a randomized, double-blind, prospective pilot study.
      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.
      • Crain S.
      • Shen K.
      Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability.
      This may contribute to opioid tolerance and, when predominant, to opioid-induced hyperalgesia.
      • Sjøgren P.
      • Jensen N.H.
      • Jensen T.S.
      Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid antagonists.
      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.
      • Wang 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.
      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.
      • Milligan E.D.
      • Watkins L.R.
      Pathological and protective roles of glia in chronic pain.
      • Ren K.
      • Dubner R.
      Neuron-glia crosstalk gets serious: role in pain hypersensitivity.
      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.
      • Yang 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.
      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.
      • Twycross R.
      • Wilcock A.
      • Toller C.S.
      Symptom management in advanced cancer.
      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).
      • Foster B.
      • Twycross R.
      • Mihalyo M.
      • Wilcock A.
      Buprenorphine.
      Naloxone has been reported to be only partially effective in reversing the effects of tramadol.
      • Raffa 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.
      • Shipton E.A.
      Tramadol - present and future.
      However, in a series of 11 patients with a tramadol overdose, seven had a good response to naloxone, and only one had no response.
      • Marquardt K.A.
      • Alsop J.A.
      • Albertson T.E.
      Tramadol exposures reported to statewide poison control system.
      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.
      • Horng 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.
      Alternatively, because pulmonary edema is almost universal in fatal opioid overdose,
      • Ridgway Z.A.
      • Pountney A.J.
      Acute respiratory distress syndrome induced by oral methadone managed with non-invasive ventilation.
      • Feeney C.
      • Ani C.
      • Sharma N.
      • Frohlich T.
      Morphine-induced cardiogenic shock.
      naloxone, by increasing respiratory rate and tidal volume, may simply unmask pulmonary edema which has developed secondary to severe hypoxemia and acidemia.
      • Clarke S.F.
      • Dargan P.I.
      • Jones A.L.
      Naloxone in opioid poisoning: walking the tightrope.
      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.
      • Paranthaman S.K.
      • Khan F.
      Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage.
      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.
      • Verebey K.
      The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.
      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).
      • Volpicelli J.R.
      • Alterman A.I.
      • Hayashida M.
      • O'Brien C.P.
      Naltrexone in the treatment of alcohol dependence.
      • Swift R.M.
      • Whelihan W.
      • Kuznetsov O.
      • Buongiorno G.
      • Hsuing H.
      Naltrexone-induced alterations in human ethanol intoxication.
      • Krupitsky E.
      • Nunes E.V.
      • Ling W.
      • et al.
      Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial.
      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)
        • Webster 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.
      • Targinact® (oxycodone + naloxone)
        Oxycodone.
      • OxyNal® (oxycodone + naltrexone).
        • Johnson F.
        • Setnik B.
        Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.
        • Webster L.
        Update on abuse-resistant and abuse-deterrent approaches to opioid formulations.
      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.
      • McNicol E.D.
      Mu-opioid antagonists for opioid-induced bowel dysfunction.
      • Becker G.
      • Blum H.E.
      Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.
      In the past, PO naloxone and naltrexone have been used to correct delayed gastric emptying and constipation.
      • McNicol E.D.
      Mu-opioid antagonists for opioid-induced bowel dysfunction.
      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).
      • Ford A.C.
      • Brenner D.M.
      • Schoenfeld P.S.
      Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis.
      Because constipation in advanced disease is generally multifactorial in origin,
      • Larkin 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.
      methylnaltrexone augments rather than replaces laxatives. Off-label uses of methylnaltrexone include opioid-induced constipation in postoperative
      • Deibert P.
      • Xander C.
      • Blum H.E.
      • Becker G.
      Methylnaltrexone: the evidence for its use in the management of opioid-induced constipation.
      • Anissian 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.
      or non-surgical critical care patients
      • Sawh S.B.
      • Selvaraj I.P.
      • Danga A.
      • et al.
      Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients.
      and opioid-related acute colonic pseudo-obstruction.
      • Weinstock L.B.
      • Chang A.C.
      Methylnaltrexone for treatment of acute colonic pseudo-obstruction.
      Methylnaltrexone also may improve other peripheral effects of opioids, e.g., urinary retention.
      • Deibert P.
      • Xander C.
      • Blum H.E.
      • Becker G.
      Methylnaltrexone: the evidence for its use in the management of opioid-induced constipation.
      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.
      Oxycodone.
      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.
      • Davis M.
      Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics.
      • Metze 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.
      • Jones E.A.
      • Neuberger J.
      • Bergasa N.V.
      Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.
      • Tandon 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.
      Opioid antagonists counteract the increased tone, and thus relieve the pruritus.
      Naloxone by CIVI/CSCI decreases scratching activity by patients with cholestatic pruritus
      • Bergasa N.V.
      • Talbot T.L.
      • Alling D.W.
      • et al.
      A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.
      • Bergasa N.V.
      • Alling D.W.
      • Talbot T.L.
      • et al.
      Effects of naloxone infusions in patients with the pruritus of cholestasis.
      • Kumar N.
      • Garg N.
      • Bailey A.
      Opiate receptor antagonists for treatment of severe pruritus associated with advanced cholestatic liver disease.
      and has a place in the emergency treatment of acute exacerbations of cholestatic pruritus. PO naltrexone
      • Wolfhagen F.H.
      • Sternieri E.
      • Hop W.C.
      • et al.
      Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study.
      • Terg 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.
      (or nalmefene
      • Bergasa 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.
      ) can then be used long-term.
      However, opioid antagonists can precipitate an opioid withdrawal-like reaction in patients with cholestasis, including hallucinations and dysphoria.
      • Jones E.A.
      • Neuberger J.
      • Bergasa N.V.
      Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.
      • Jones E.
      • Dekker L.
      Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.
      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.
      • McRae C.A.
      • Prince M.I.
      • Hudson M.
      • et al.
      Pain as a complication of use of opiate antagonists for symptom control in cholestasis.
      Thus, patients with cholestatic jaundice and pruritus and severe pain should not be treated with an opioid antagonist.
      • Lonsdale-Eccles A.A.
      • Carmichael A.J.
      Opioid antagonist for pruritus of cholestasis unmasking bony metastases.
      Instead, an alternative treatment for pruritus should be used (e.g., sertraline, rifampicin
      • Tandon 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.
      • Chan K.Y.
      • Li C.W.
      • Wong H.
      • et al.
      Use of sertraline for antihistamine-refractory uremic pruritus in renal palliative care patients.
      ) 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.
      • Juby L.D.
      • Wong V.S.
      • Losowsky M.S.
      Buprenorphine and hepatic pruritus.
      • Reddy L.
      • Krajnik M.
      • Zylicz Z.
      Transdermal buprenorphine may be effective in the treatment of pruritus in primary biliary cirrhosis.
      • Marinangeli F.
      • Guetti C.
      • Angeletti C.
      • et al.
      Intravenous naloxone plus transdermal buprenorphine in cancer pain associated with intractable cholestatic pruritus.
      • Zylicz Z.
      • Stork N.
      • Krajnik M.
      Severe pruritus of cholestasis in disseminated cancer: developing a rational treatment strategy. A case report.
      Sometimes ultra-low doses of naloxone or naltrexone improved both the pruritus and the pain.
      • Jones E.A.
      • Zylicz Z.
      Treatment of pruritus caused by cholestasis with opioid antagonists.
      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).
      • Manenti L.
      • Tansinda P.
      • Vaglio A.
      Uraemic pruritus: clinical characteristics, pathophysiology and treatment.
      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.
      • Kumagai H.
      • et al.
      Endogenous opioid system in uraemic patients.
      • Odou P.
      • Azar R.
      • Luyckx M.
      • Brunet C.
      • Dine T.
      A hypothesis for endogenous opioid peptides in uraemic pruritus: role of enkephalin.
      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.
      • Wikström B.
      • Gellert R.
      • Ladefoged S.D.
      • et al.
      Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies.
      Naltrexone also has been tried in this setting.
      • Phan N.Q.
      • Bernhard J.D.
      • Luger T.A.
      • Ständer S.
      Antipruritic treatment with systemic u-opioid receptor antagonists; a review.
      However, RCTs have given conflicting results, e.g., benefit was seen in uremic patients with very severe pruritus
      • Peer G.
      • Kivity S.
      • Agami O.
      • et al.
      Randomised crossover trial of naltrexone in uraemic pruritus.
      but not in those with moderately severe pruritus.
      • Pauli-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.
      One explanation is that, in uremia, an opioid mechanism is important only in severe pruritus. The fact that naltrexone is non-selective and antagonizes both μ- and κ-opioid receptors also may be relevant.
      In an open study of patients with various skin and systemic disorders associated with pruritus, good relief was obtained with naltrexone in 70% of patients.
      • Metze 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.
      However, in the absence of controlled data, the results should be interpreted with caution. Pruritus associated with chronic disease generally requires alternative specific measures.
      Opioid antagonists.
      Ultra-low dose naloxone also is used to relieve pruritus caused by spinal opioids, when other treatments have failed.
      Spinal analgesia.
      Miscellaneous: Naloxone is reported to benefit patients with septic shock,
      • Peters W.P.
      • Johnson M.W.
      • Friedman P.A.
      • Mitch W.E.
      Pressor effect of naloxone in septic shock.
      morphine-induced peripheral vasodilation,
      • Cohen R.A.
      • Coffman J.D.
      Naloxone reversal of morphine-induced peripheral vasodilatation.
      ischemic central neurological deficits
      • Baskin D.S.
      • Hosobuchi Y.
      Naloxone reversal of ischaemic neurological deficits in man.
      • Bousigue J.Y.
      • Giraud L.
      • Fournié D.
      • Trémoulet M.
      Naloxone reversal of neurological deficit.
      and post-stroke central pain.
      • Ray D.
      • Tai Y.
      Infusions of naloxone in thalamic pain.
      Endogenous opioids inhibit cell proliferation, an effect which intermittent low-dose naltrexone appears to augment by provoking a compensatory elevation in opioid growth factor (OGF, an enkephalin) and OGF receptor, (a non-classical opioid receptor). This interaction impacts upon the cell cycle, inhibiting proliferation. The potential roles of low-dose naltrexone and OGF in cancer and auto-immune diseases (e.g., multiple sclerosis, Crohn's disease) are being explored.
      • Smith J.P.
      • Bingaman S.I.
      • Mauger D.T.
      • et al.
      Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer.
      • Donahue R.N.
      • McLaughlin P.J.
      • Zagon I.S.
      Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.
      • McLaughlin P.J.
      • Zagon I.S.
      The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and disease.
      Pharmacokinetics: Table 1 contains selected pharmacokinetic data. Compared with naloxone, naltrexone has a higher PO bioavailability and a longer duration of action; it undergoes extensive first-pass metabolism.
      • Gonzalez J.
      • Brogden R.
      Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence.
      • Crabtree B.
      Review of naltrexone: a long-acting opiate antagonist.
      The major metabolite, 6-β-naltrexol, is a neutral antagonist, i.e., it inhibits activation of opioid receptors but, unlike naloxone and naltrexone, it does not suppress basal receptor signaling, thereby reducing the risk of severe withdrawal. The antagonist effect of 6-β-naltrexol also shows peripheral selectivity. Accordingly, it may be developed commercially as a treatment for opioid-induced GI disorders.
      • Yancey-Wrona J.
      • Dallaire B.
      • Bilsky E.
      • et al.
      6beta-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study.
      Table 1Pharmacokinetic profiles of selected opioid antagonists
      NaloxoneNaltrexone
      Bioavailability (%)6 PO5–40 PO
      Onset of action1–2min IV; 2–5min SC/IMmay precipitate withdrawal symptoms in <5min in opioid-dependent patients
      Time to peak plasma concentration (h)1–2 PO
      Half-life (h)about 14; 13 for 6-β-naltrexol
      • Gutstein H.B.
      • Akil H.
      Opioid analgesics.
      Duration of actionIV 15–90min1–3 days

      Cautions

      For full list, see manufacturers' Prescribing Information.
      In patients receiving opioids for pain relief, naloxone should not be used for drowsiness and/or delirium which is not life-threatening because of the danger of reversing the opioid analgesia and precipitating a major physical withdrawal syndrome. Instead, omit or reduce the next regular dose, and subsequently continue at a reduced dose.
      The use of naltrexone also will impede opioid analgesia (see below),
      • Vickers A.P.
      • Jolly A.
      Naltrexone and problems in pain management.
      and can precipitate an opioid withdrawal-like syndrome in patients with cholestatic pruritus.
      Naltrexone may cause occasional hepatotoxicity;
      • Mitchell J.
      Naltrexone and hepatotoxicity.
      the manufacturer advises checking LFTs before and at intervals during treatment.

      Undesirable Effects

      For full list, see manufacturers' Prescribing Information.
      Naloxone: nausea and vomiting; occasionally severe hypertension, pulmonary edema (see above), rarely tachycardia, arrhythmias, and even cardiac arrest.
      • Partridge B.L.
      • Ward C.F.
      Pulmonary oedema following low-dose naloxone administration.
      Naltrexone: very common (>10% in detoxifying opioid addicts) insomnia, headaches, anxiety, nausea and vomiting, intestinal colic, lack of energy, joint and muscle pain.
      The long-term use of naltrexone increases the concentration of opioid receptors in the CNS and results in a temporary enhanced response to the subsequent administration of opioid analgesics.
      • Yoburn B.C.
      • Luke M.C.
      • Pasternak G.W.
      • Inturrisi C.E.
      Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE.
      The management of severe acute and postoperative pain in patients receiving long-term naltrexone requires careful consideration and detailed planning (Box A).
      • Vickers A.P.
      • Jolly A.
      Naltrexone and problems in pain management.
      Management of acute pain in patients receiving naltrexone
      Elective surgery
      The use of naltrexone must be identified well before the operation.
      Ensure effective liaison between the substance misuse and acute pain teams.
      Consider switching patients on IM depot injections to PO tablets before surgery.
      For minor surgery, when non-opioids are considered sufficient to manage the postoperative pain, leave SC pellet in situ; if severe postoperative pain anticipated, remove SC pellet.
      Discontinue PO naltrexone 72h before the operation.
      Maximize the use of non-opioid analgesics, e.g., IV paracetamol, NSAID.
      Note: if an opioid analgesic is required, a larger than usual dose may be needed but, conversely, there may be an increased response to opioids (see Pharmacology above).
      Unexpected severe acute pain, e.g., trauma, emergency surgery
      If possible use non-opioid analgesics, e.g.:
      • IV paracetamol and/or NSAID
      • ketamine 100microgram/kg IV every 5min until satisfactory analgesia obtained, plus a single dose of midazolam 20–40microgram/kg IV to minimize dysphoria; may be repeated after 30min; give further midazolam only if dysphoria present.
      Note: there is a risk of marked sedation when ketamine and midazolam are combined in this way; to be used only by those competent in airway management.
      If venous access is difficult, ketamine can be given SC; use the same doses as for IV but allow 15min between doses.
      The above are generally used to achieve rapid pain relief until other measures can be instituted, e.g.:
      • local anesthetic blocks
      • epidural analgesia (local anesthetic ± clonidine).
      Methylnaltrexone: common abdominal pain/colic (generally mild-moderate),
      • Slatkin N.E.
      • Lynn R.
      • Su C.
      • Wang W.
      • Israel R.J.
      Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials.
      diarrhea, flatulence, nausea (these generally resolve after a bowel movement), dizziness (postural hypotension can occur). Rare syncope, severe diarrhea and cardiovascular collapse, and GI perforation (stomach, small and large bowel).
      • Mackey A.C.
      • Green L.
      • Greene P.
      • Avigan M.
      Methylnaltrexone and gastrointestinal perforation.

      Dose and Use

      Naloxone is best given IV but, if not practical, may be given IM or SC.

      Opioid overdose (naloxone)

      Dose recommendations vary, and the following is offered as a guide:
      • start with 400microgram–2mg IV every 2–3min p.r.n., up to a total of 10mg
      • if necessary, set up an IVI set to deliver an hourly dose which is 50–100% of the stat dose which had previously maintained satisfactory ventilation for ≥15min
      • the recommended IVI concentration is 200microgram/mL, diluted in 0.9% saline or 5% glucose
      • titrate the IVI as necessary.
      Although significant respiratory depression is rarely seen with clinically recommended doses of buprenorphine, serious or fatal respiratory depression has occurred in addicts abusing buprenorphine, generally high dose IV and/or in combination with benzodiazepines or other CNS depressants, e.g., alcohol.
      • Kintz P.
      Deaths involving buprenorphine: a compendium of French cases.
      • Häkkinen M.
      • Launiainen T.
      • Vuori E.
      • Ojanperä I.
      Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning.
      Because buprenorphine has very strong receptor affinity (reflected in its high relative potency with morphine), naloxone in standard doses does not reverse the effects of buprenorphine and higher doses must be used (Box B).
      • Dahan A.
      • Aarts L.
      • Smith T.W.
      Incidence, reversal, and prevention of opioid-induced respiratory depression.
      The non-specific respiratory stimulant doxapram also can be used, 1–1.5mg/kg IV over 30sec, repeated if necessary at hourly intervals or 1.5–4mg/min CIVI.
      • Dahan A.
      • Aarts L.
      • Smith T.W.
      Incidence, reversal, and prevention of opioid-induced respiratory depression.
      • Orwin J.M.
      The effect of doxapram on buprenorphine induced respiratory depression.
      Reversal of buprenorphine-induced respiratory depression
      Discontinue buprenorphine (stop CSCI/CIVI, remove TD patch).
      Give oxygen by mask.
      Give IV naloxone 2mg stat over 90sec.
      Start naloxone 4mg/h by CIVI.
      Continue CIVI until the patient's condition is satisfactory (probably <90min).
      Monitor the patient frequently for the next 24h, and restart CIVI if respiratory depression recurs.
      If the patient's condition remains satisfactory, restart with a lower dose buprenorphine, e.g., half the previous dose.
      If following the administration of naloxone there is unexpected breathlessness and persistent hypoxemia despite oxygen, the possibility of pulmonary edema should be considered. Delayed-onset pulmonary edema (48h after overdose) also may occur, associated with acute cardiomyopathy, and possibly the result of hypoxemic cardiac muscle damage.
      • Paranthaman S.K.
      • Khan F.
      Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage.
      Treat as necessary with oxygen, IV furosemide, IVI nitrates, and ventilation. The pulmonary edema generally responds to these measures and resolves within 24–48h.

      Reversal of respiratory depression caused by the medicinal use of opioids (naloxone)

      If respiratory rate ≥8 breaths/min, and the patient easily rousable and not cyanosed, adopt a policy of “wait and see”; consider omitting or reducing the next regular dose, and subsequently continuing at a reduced dose.
      If the overdose is associated with a long-acting opioid (particularly methadone or dextropropoxyphene) or an SR formulation, the duration of action of the opioid will exceed that of naloxone. Even if there is an initial response to naloxone, further IV doses are likely to be needed, and it may be necessary to continue treatment with a closely monitored IVI of naloxone for up to 24h, and sometimes longer.
      In patients taking a strong opioid for severe pain and who have become physically dependent, naloxone 400microgram (a standard ampoule) will precipitate an acute withdrawal syndrome, severe pain with hyperalgesia, and marked agitation.
      • Cleary J.
      Incidence and characteristics of naloxone administration in medical oncology patients with cancer pain.
      Small doses must be used. Thus, if respiratory rate <8 breaths/min, and the patient comatose/unconscious and/or cyanosed:
      • give 100–200microgram IV stat
      • if necessary, give 100microgram every 2min until respiratory function is satisfactory
      • further IV doses should be given after 1–2h if there is concern that further absorption of the opioid will result in delayed respiratory depression.
      The dose is titrated to maintain adequate respiratory function, not level of consciousness. The American Pain Society recommends even smaller doses:
      • Miaskowski C.
      • Bair M.
      • Chou R.
      • et al.
      Principles of analgesic use in the treatment of acute pain and cancer pain.
      • dilute a 1mL ampoule containing naloxone 400microgram to 10mL with 0.9% saline for injection
      • administer 0.5mL (20microgram) IV every 2min until the patient's respiratory status is satisfactory
      • further doses may be necessary because naloxone is shorter-acting than most opioid analgesics.
      Consider the possible cause(s) of the opioid overdose, e.g., reduced elimination because of renal impairment (morphine, hydromorphone) or accumulation because of a long half-life (methadone). Wait until there has been a sustained improvement in consciousness before restarting with a lower opioid dose. It may be preferable to switch to another opioid; seek specialist advice.

      Treatment of opioid-induced constipation (methylnaltrexone)

      Methylnaltexone is relatively expensive and should be considered only as a supplement to a stimulant laxative (e.g., senna)
      • Twycross R.
      • Sykes N.
      • Mihalyo M.
      • Wilcock A.
      Stimulant laxatives and opioid-induced constipation.
      when an optimized dose of the latter is insufficient. A survey in the USA found that about one quarter of prescriptions for methylnaltrexone (mainly by generalists) were inappropriate with regard to indication or dose.
      • Watkins J.L.
      • Eckmann K.R.
      • Mace M.L.
      • et al.
      Utilization of methylnaltrexone (Relistor) for opioid-induced constipation in an oncology hospital.
      Methylnaltrexone is contraindicated in cases of known or suspected bowel obstruction; it should be used with caution in patients with conditions which may predispose to perforation (e.g., GI cancer, peptic ulcer, colonic pseudo-obstruction). Between 1/3–1/2 of patients given methylnaltrexone defecate within 30min–4h without loss of analgesia or the development of opioid withdrawal symptoms.
      • Portenoy R.K.
      • Thomas J.
      • Moehl Boatwright M.L.
      • et al.
      Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study.
      • Thomas J.
      • Karver S.
      • Cooney G.A.
      • et al.
      Methylnaltrexone for opioid-induced constipation in advanced illness.
      • Slatkin N.
      • Thomas J.
      • Lipman A.G.
      • et al.
      Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients.
      • Michna E.
      • Blonsky E.R.
      • Schulman S.
      • et al.
      Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.
      • Candy B.
      • Jones L.
      • Goodman M.L.
      • Drake R.
      • Tookman A.
      Laxatives or methylnaltrexone for the management of constipation in palliative care patients.
      Dose recommendations:
      • for patients weighing 38–62kg, start with 8mg on alternate days
      • for patients weighing 62–114kg, start with 12mg on alternate days
      • outside this range, give 150microgram/kg on alternate days
      • the interval between administrations can be varied, either extended or reduced, but not more than once daily
      The dose of methylnaltrexone should be halved in severe renal impairment (creatinine cleareance <30mL/min).

      Cholestatic pruritus (naloxone, nalmefene, naltrexone)

      To try and avoid or minimize an opioid withdrawal-like syndrome, start with a low dose. Although some recommend the initial use of naloxone, others have successfully used naltrexone de novo 12.5–25mg b.i.d. and subsequently titrated as below:
      • start with a low dose of naloxone by CIVI, e.g., 0.002microgram/kg/min (about 160–200microgram/24h)52; long-term administration by CSCI also has been reported
        • Kumar N.
        • Garg N.
        • Bailey A.
        Opiate receptor antagonists for treatment of severe pruritus associated with advanced cholestatic liver disease.
      • if no withdrawal-like symptoms occur, the rate can be doubled every 3–4h; but if symptoms occur, continue with the current dose until resolved
      • after 18–24h, when a rate known to be associated with opioid antagonistic effects is reached (0.2microgram/kg/min), the infusion is stopped and naltrexone 12.5–25mg PO b.i.d. is started)
        • Jones E.A.
        • Neuberger J.
        • Bergasa N.V.
        Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.
        • Terg 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.
        • Jones E.
        • Dekker L.
        Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.
      • the dose is increased every few days until a satisfactory clinical response is obtained; at this stage, the effective dose should be consolidated into a single daily maintenance dose
      • the effective dose range for PO naltrexone is 25–250mg once daily;
        • Jones E.A.
        • Neuberger J.
        • Bergasa N.V.
        Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.
      • some centers use PO nalmefene: start with 2mg b.i.d.; double the dose every 2 days until pruritus is relieved or no further improvement; individual maximum doses 30–120mg b.i.d.
        • Bergasa N.V.
        • Schmitt J.M.
        • Talbot T.L.
        • et al.
        Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.

      Uremic pruritus (naltrexone)

      • start with 50mg once daily
        • Peer G.
        • Kivity S.
        • Agami O.
        • et al.
        Randomised crossover trial of naltrexone in uraemic pruritus.
        • Pauli-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.
      • if ineffective after 1 week, consider increasing dose to 100mg once daily.

      Supply

      Naloxone
      Naloxone (generic)
      Injection 400microgram/mL, 1mL vial = $13; 1mL syringe = $9; 10mL vial = $82.
      Injection 1mg/mL, 2mL syringe = $20.
      Naltrexone
      Naltrexone (generic)
      Tablets (scored) 50mg, 28 days @ 50mg once daily = $120.
      ReVia® (DuPont)
      Tablets (scored) 50mg, 28 days @ 50mg once daily = $252.
      Methylnaltexone
      Relistor® (Wyeth)
      Injection 8mg, 0.4mL vial = $72; 12mg, 0.6mL vial = $72.

      References

        • Wolfhagen F.H.
        • Sternieri E.
        • Hop W.C.
        • et al.
        Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study.
        Gastroenterology. 1997; 113: 1264-1269
        • Peer G.
        • Kivity S.
        • Agami O.
        • et al.
        Randomised crossover trial of naltrexone in uraemic pruritus.
        Lancet. 1996; 348: 1552-1554
        • Pauli-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: 514-519
        • Choi 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: 71-90
        • Gan 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: 1075-1081
        • Joshi 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: 1007-1011
        • Cepeda 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: 41-46
        • Maxwell 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: 953-958
        • Murphy 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: 321-327
        • Levine J.D.
        • Gordon N.C.
        • Fields H.L.
        Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain.
        Nature. 1979; 278: 740-741
        • Levine J.
        • Gordon N.
        Synergism between the analgesic actions of morphine and pentazocine.
        Pain. 1988; 33: 369-372
        • Hill R.G.
        Multiple opioid receptors and their ligands.
        Frontiers of Pain. 1992; 4: 1-4
        • Chindalore 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: 392-399
        • Largent-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: 700-713
        • Hay 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: 293-298
        • Cruciani 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: 491-494
        • Hamann 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: 137-144
        • Crain S.
        • Shen K.
        Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability.
        Pain. 2000; 84: 121-131
        • Sjøgren P.
        • Jensen N.H.
        • Jensen T.S.
        Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid antagonists.
        Pain. 1994; 59: 313-316
        • Wang 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: e4282
        • Milligan E.D.
        • Watkins L.R.
        Pathological and protective roles of glia in chronic pain.
        Nat Rev Neurosci. 2009; 10: 23-36
        • Ren K.
        • Dubner R.
        Neuron-glia crosstalk gets serious: role in pain hypersensitivity.
        Curr Opin Anaesthesiol. 2008; 21: 570-579
        • Yang 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: 1490-1500
        • Twycross R.
        • Wilcock A.
        • Toller C.S.
        Symptom management in advanced cancer.
        4th ed. palliativedrugs.com Ltd., Nottingham2009: 43-45
        • Foster B.
        • Twycross R.
        • Mihalyo M.
        • Wilcock A.
        Buprenorphine.
        J Pain Symptom Manage. 2013; 45: 939-949
        • Raffa 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: 275-285
        • Shipton E.A.
        Tramadol - present and future.
        Anaesth Intensive Care. 2000; 28: 363-374
        • Marquardt K.A.
        • Alsop J.A.
        • Albertson T.E.
        Tramadol exposures reported to statewide poison control system.
        Ann Pharmacother. 2005; 39: 1039-1044
        • Horng 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: 155-157
        • Ridgway Z.A.
        • Pountney A.J.
        Acute respiratory distress syndrome induced by oral methadone managed with non-invasive ventilation.
        Emerg Med J. 2007; 24: 681
        • Feeney C.
        • Ani C.
        • Sharma N.
        • Frohlich T.
        Morphine-induced cardiogenic shock.
        Ann Pharmacother. 2011; 45: e30
        • Clarke S.F.
        • Dargan P.I.
        • Jones A.L.
        Naloxone in opioid poisoning: walking the tightrope.
        Emerg Med J. 2005; 22: 612-616
        • Paranthaman S.K.
        • Khan F.
        Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage.
        Chest. 1976; 69: 117-119
        • Verebey K.
        The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.
        NIDA Res Monogr. 1981; 28: 147-158
        • Volpicelli J.R.
        • Alterman A.I.
        • Hayashida M.
        • O'Brien C.P.
        Naltrexone in the treatment of alcohol dependence.
        Arch Gen Psychiatry. 1992; 49: 876-880
        • Swift R.M.
        • Whelihan W.
        • Kuznetsov O.
        • Buongiorno G.
        • Hsuing H.
        Naltrexone-induced alterations in human ethanol intoxication.
        Am J Psychiatry. 1994; 151: 1463-1467
        • Krupitsky 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: 1506-1513
        • Webster 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: 734-746
      1. Oxycodone.
        in: Twycross R. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 424-429
        • Johnson F.
        • Setnik B.
        Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.
        Pain Physician. 2011; 14: 391-406
        • Webster L.
        Update on abuse-resistant and abuse-deterrent approaches to opioid formulations.
        Pain Med. 2009; 10: S124-S133
        • McNicol E.D.
        Mu-opioid antagonists for opioid-induced bowel dysfunction.
        Cochrane Database Syst Rev. 2008; : CD006332
        • Becker G.
        • Blum H.E.
        Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.
        Lancet. 2009; 373: 1198-1206
        • Ford 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: 1566-1574
        • Larkin 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: 796-807
        • Deibert 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: 247-258
        • Anissian 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: 67-72
        • Sawh 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: 255-259
        • Weinstock L.B.
        • Chang A.C.
        Methylnaltrexone for treatment of acute colonic pseudo-obstruction.
        J Clin Gastroenterol. 2011; 45: 883-884
        • Davis M.
        Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics.
        Clin Pharmacokinet. 2007; 46: 825-850
        • Metze 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: 533-539
        • Jones 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: 547-552
        • Tandon 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: 1528-1536
        • Bergasa 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: 544-549
        • Bergasa 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: 161-167
        • Kumar N.
        • Garg N.
        • Bailey A.
        Opiate receptor antagonists for treatment of severe pruritus associated with advanced cholestatic liver disease.
        J Palliat Med. 2013; 16: 122-123
        • Terg 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: 717-722
        • Bergasa 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: 431-434
        • Jones E.
        • Dekker L.
        Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.
        Gastroenterology. 2000; 118: 431-432
        • McRae 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: 591-596
        • Lonsdale-Eccles A.A.
        • Carmichael A.J.
        Opioid antagonist for pruritus of cholestasis unmasking bony metastases.
        Acta Derm Venereol. 2009; 89: 90
        • Chan 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: 966-970
        • Juby L.D.
        • Wong V.S.
        • Losowsky M.S.
        Buprenorphine and hepatic pruritus.
        Br J Clin Pract. 1994; 48: 331
        • Reddy 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: 455-456
        • Marinangeli 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-e8
        • Zylicz 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: 100-103
        • Jones E.A.
        • Zylicz Z.
        Treatment of pruritus caused by cholestasis with opioid antagonists.
        J Palliat Med. 2005; 8: 1290-1294
        • Manenti L.
        • Tansinda P.
        • Vaglio A.
        Uraemic pruritus: clinical characteristics, pathophysiology and treatment.
        Drugs. 2009; 69: 251-263
        • Kumagai 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)
        • Odou 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: 1953-1954
        • Wikström 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: 3742-3747
        • Phan 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: 680-688
      2. Opioid antagonists.
        in: Twycross R. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 328-336
      3. Spinal analgesia.
        in: Twycross R. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 509-517
        • Peters W.P.
        • Johnson M.W.
        • Friedman P.A.
        • Mitch W.E.
        Pressor effect of naloxone in septic shock.
        Lancet. 1981; 1: 529-532
        • Cohen R.A.
        • Coffman J.D.
        Naloxone reversal of morphine-induced peripheral vasodilatation.
        Clin Pharmacol Ther. 1980; 28: 541-544
        • Baskin D.S.
        • Hosobuchi Y.
        Naloxone reversal of ischaemic neurological deficits in man.
        Lancet. 1981; 2: 272-275
        • Bousigue J.Y.
        • Giraud L.
        • Fournié D.
        • Trémoulet M.
        Naloxone reversal of neurological deficit.
        Lancet. 1982; 2: 618-619
        • Ray D.
        • Tai Y.
        Infusions of naloxone in thalamic pain.
        BMJ. 1988; 296: 969-970
        • Smith J.P.
        • Bingaman S.I.
        • Mauger D.T.
        • et al.
        Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer.
        Open Access J Clin Trials. 2010; 2010: 37-48
        • Donahue R.N.
        • McLaughlin P.J.
        • Zagon I.S.
        Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.
        Exp Biol Med. 2011; 236: 1036-1050
        • McLaughlin P.J.
        • Zagon I.S.
        The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and disease.
        Biochem Pharmacol. 2012; 84: 746-755
        • Gonzalez J.
        • Brogden R.
        Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence.
        Drugs. 1988; 35: 192-213
        • Crabtree B.
        Review of naltrexone: a long-acting opiate antagonist.
        Clin Pharm. 1984; 3: 273-280
        • Yancey-Wrona J.
        • Dallaire B.
        • Bilsky E.
        • et al.
        6beta-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study.
        Pain Med. 2011; 12: 1727-1737
        • Gutstein H.B.
        • Akil H.
        Opioid analgesics.
        in: Hardman J.G. Limbird L.E. Gilman A.G. Goodman & Gilman's The pharmacological basis of therapeutics. 10th ed. McGraw-Hill, New York2001: 569-620
        • Vickers A.P.
        • Jolly A.
        Naltrexone and problems in pain management.
        BMJ. 2006; 332: 132-133
        • Mitchell J.
        Naltrexone and hepatotoxicity.
        Lancet. 1986; 1: 1215
        • Partridge B.L.
        • Ward C.F.
        Pulmonary oedema following low-dose naloxone administration.
        Anesthesiology. 1986; 65: 709-710
        • Yoburn B.C.
        • Luke M.C.
        • Pasternak G.W.
        • Inturrisi C.E.
        Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE.
        Life Sci. 1988; 43: 1319-1324
        • Slatkin N.E.
        • Lynn R.
        • Su C.
        • Wang W.
        • Israel R.J.
        Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials.
        J Pain Symptom Manage. 2011; 42: 754-760
        • Mackey A.C.
        • Green L.
        • Greene P.
        • Avigan M.
        Methylnaltrexone and gastrointestinal perforation.
        J Pain Symptom Manage. 2010; 40: e1-e3
      4. Sweetman S.C. Martindale: the complete drug reference (online edition). Pharmaceutical Press, London2012 (Available from) (Accessed October 15, 2013)
        • Kintz P.
        Deaths involving buprenorphine: a compendium of French cases.
        Forensic Sci Int. 2001; 121: 65-69
        • Häkkinen M.
        • Launiainen T.
        • Vuori E.
        • Ojanperä I.
        Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning.
        Eur J Clin Pharmacol. 2012; 68: 301-309
      5. Budd K. Raffa R. Buprenorphine - the unique opioid analgesic. Georg Thieme Verlag, Stuttgart2005: 134
        • Dahan A.
        • Aarts L.
        • Smith T.W.
        Incidence, reversal, and prevention of opioid-induced respiratory depression.
        Anesthesiology. 2010; 112: 226-238
        • Orwin J.M.
        The effect of doxapram on buprenorphine induced respiratory depression.
        Acta Anaesthesiol Belg. 1977; 28: 93-106
        • Cleary J.
        Incidence and characteristics of naloxone administration in medical oncology patients with cancer pain.
        J Pharm Care Pain Symptom Control. 2000; 8: 65-73
        • Miaskowski C.
        • Bair M.
        • Chou R.
        • et al.
        Principles of analgesic use in the treatment of acute pain and cancer pain.
        6th ed. American Pain Society, Skokie, IL2008: 31
        • Twycross R.
        • Sykes N.
        • Mihalyo M.
        • Wilcock A.
        Stimulant laxatives and opioid-induced constipation.
        J Pain Symptom Manage. 2012; 43: 306-313
        • Watkins J.L.
        • Eckmann K.R.
        • Mace M.L.
        • et al.
        Utilization of methylnaltrexone (Relistor) for opioid-induced constipation in an oncology hospital.
        P T. 2011; 36: 33-36
        • Portenoy R.K.
        • Thomas J.
        • Moehl Boatwright M.L.
        • et al.
        Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study.
        J Pain Symptom Manage. 2008; 35: 458-468
        • Thomas J.
        • Karver S.
        • Cooney G.A.
        • et al.
        Methylnaltrexone for opioid-induced constipation in advanced illness.
        N Engl J Med. 2008; 358: 2332-2343
        • Slatkin N.
        • Thomas J.
        • Lipman A.G.
        • et al.
        Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients.
        J Support Oncol. 2009; 7: 39-46
        • Michna E.
        • Blonsky E.R.
        • Schulman S.
        • et al.
        Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.
        J Pain. 2011; 12: 554-562
        • Candy B.
        • Jones L.
        • Goodman M.L.
        • Drake R.
        • Tookman A.
        Laxatives or methylnaltrexone for the management of constipation in palliative care patients.
        Cochrane Database Syst Rev. 2011; : CD003448
        • Bergasa N.V.
        • Schmitt J.M.
        • Talbot T.L.
        • et al.
        Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.
        Hepatology. 1998; 27: 679-684