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Proceedings of the Symposium “Updates of the Clinical Pharmacology of Opioids with Special Attention to Long-Acting Drugs”| Volume 29, ISSUE 5, SUPPLEMENT , 57-66, May 01, 2005

Hydromorphone

  • Alison Murray
    Affiliations
    Department of Family Medicine (A.M.), Division of Palliative Medicine (A.M., N.A.H.), and Departments of Clinical Neurosciences and Medicine (N.A.H.), University of Calgary; and Tom Baker Cancer Center (A.M., N.A.H.), Calgary, Alberta, Canada
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  • Neil A. Hagen
    Correspondence
    Address reprint requests to: Neil A. Hagen, MD, FRCPC, 1331-29 St. NW, Calgary, Alberta, Canada T2N 4N2.
    Affiliations
    Department of Family Medicine (A.M.), Division of Palliative Medicine (A.M., N.A.H.), and Departments of Clinical Neurosciences and Medicine (N.A.H.), University of Calgary; and Tom Baker Cancer Center (A.M., N.A.H.), Calgary, Alberta, Canada
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      Abstract

      Hydromorphone is a semi-synthetic opioid that has been used widely for acute pain, chronic cancer pain and to a lesser extent, in chronic nonmalignant pain. Its pharmacokinetics and pharmacodynamics have been well studied, including immediate release oral preparations, a variety of slow release oral preparations, as well as administration through intravenous, subcutaneous, epidural, intrathecal and other routes. It is known to be metabolized to analgesically inactive metabolites that have been associated with neuroexcitatory states and other toxicity. There is no evidence that hydromorphone has any greater abuse liability than other opioids. Further research is needed to address remaining areas of uncertainty: equianalgesic ratios; relative risk of toxicity compared with other opioids, its use in nonmalignant pain, and the role of specific hydromorophone metabolites in the development of toxicity, particularly in association with organ failure.

      History

      Hydromorphone is a semi-synthetic opioid agonist and a hydrogenated ketone of morphine.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      It was first synthesized in Germany in 1921 and was introduced into clinical practice by 1926. Although there were over 200 publications supporting its pain relieving qualities within ten years of its introduction to clinical medicine, hydromorphone has commonly been viewed as a second-line drug to morphine in the treatment of both acute and chronic pain.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      Oral morphine is the drug of first choice for chronic cancer pain as recommended by the World Health Organization,
      • World Health Organization
      Report on cancer pain relief and palliative care.
      because of its global availability and the extensive clinical experience and pharmacokinetic and pharmacodynamic data available.
      • Sarhill N.
      • Walsh D.
      • Nelson K.A.
      Hydromorphone: pharmacology and clinical applications in cancer patients.
      Despite this recommendation, a significant proportion of patients do not achieve adequate pain relief with morphine, commonly because of unmanageable adverse effects such as nausea, delirium, or myoclonus. It has been shown that rotating from one opioid to another can improve pain control as well as reduce opioid-related toxicity, although the mechanisms are unclear.
      • Sjogren P.
      • Jensen N.H.
      • Jensen T.S.
      Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability: the application of alternate opioid therapy.
      • Manfredi P.L.
      • Borsook D.
      • Chandler S.W.
      • Payne R.
      Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations.
      • Ashby M.A.
      • Martin P.
      • Jackson K.A.
      Opioid substitution to reduce adverse effects in cancer pain management.
      Therefore, hydromorphone has a key role in the area of chronic and acute pain relief as an alternative to morphine. It is included in clinical practice guidelines for the management of pain secondary to cancer
      • World Health Organization
      Report on cancer pain relief and palliative care.
      • Jacox A.
      • Carr D.B.
      • Payne R.
      New clinical-practice guidelines for the management of pain in patients with cancer.
      and has been well studied as an analgesic for post-operative pain.
      • Chaplan S.R.
      • Duncan S.R.
      • Brodsky J.B.
      • Brose W.G.
      Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison.
      • Goodarzi M.
      Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery.
      • Carr D.B.J.
      • Jacox A.K.
      • Chapman C.R.
      • et al.
      Acute pain management: operative or medical procedures and trauma. Clinical practice guideline no. 1.
      Raymond W. Houde and Ada Rogers started an informal group called the New York Pain Group in the early 1960s and went on to co-found the American Pain Society in the late 1970s. Houde is professor emeritus at Memorial Sloan Kettering Cancer Institute and has written numerous articles on pain, its physiology, and treatment. He was involved in studies during the 1980s which elucidated the equianalgesic ratio between oral and parenteral hydromorphone, as well as the potency of hydromorphone compared to morphine.
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      However, to this day further research is ongoing to add to understanding of this drug and its clinical applications.

      Chemistry

      Hydromorphone is structurally very similar to morphine; it differs from morphine by the presence of a 6-keto group and the hydrogenation of the double bond at the 7-8 position of the molecule.
      • Babul N.
      • Darke A.C.
      • Hagen N.
      Hydromorphone metabolite accumulation in renal failure.
      Like morphine, it acts primarily on μ opioid receptors, and to a lesser degree on delta receptors. Hydromorphone does not effect kappa, sigma, or epsilon receptors.
      • Benedetti C.B.
      • Butler S.H.
      Systemic analgesics.
      μ receptors mediate the pain relieving properties of opioids but also mediate unwanted side effects, such as constipation, nausea, and respiratory depression.

      Pharmacokinetics

      Oral

      Hydromorphone is available in the following oral preparations: powder, solution, immediate-release tablet, and modified-release tablet. It is absorbed in the upper small intestine, is extensively metabolized by the liver, and has a variety of renally excreted, water-soluble metabolites. Approximately 62% of the oral dose is eliminated by the liver on first pass, partly accounting for oral bioavailability in the range of 1:2 to 1:8.
      • Vallner J.J.
      • Stewart J.T.
      • Kotzan J.A.
      • et al.
      Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects.
      For orally-administered, immediate-release preparations, the onset of action is approximately 30 minutes with a duration of action of about 4 hours.
      • Benedetti C.B.
      • Butler S.H.
      Systemic analgesics.
      For modified-release preparations, the bioavailability is similar to immediate-release preparations, with a duration of action of either 12 or 24 hours depending on the particular formulation.
      • Hagen N.
      • Thirlwell M.P.
      • Dhaliwal H.S.
      • et al.
      Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone.
      • Bruera E.
      • Sloan P.
      • Mount B.
      • et al.
      A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group.
      • Hays H.
      • Hagen N.
      • Thirlwell M.
      • et al.
      Comparative clinical efficacy and safety of immediate-release and controlled-release hydromorphone for chronic severe cancer pain.
      • Kremer A.

      Parenteral

      Hydromorphone can be administered parenterally by intravenous, intramuscular, and subcutaneous routes. The oral to parenteral equianalgesic ratio has been estimated as 5:1, although a range has been described and clearly there is a great deal of interindividual variablility.
      • Vallner J.J.
      • Stewart J.T.
      • Kotzan J.A.
      • et al.
      Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects.
      Subcutaneous administration has been found to have 78% of the bioavailability of intravenous dosing.
      • Moulin D.E.
      • Kreeft J.H.
      • Murray-Parsons N.
      • Bouquillon A.I.
      Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain.
      Onset of action of hydromorphone after intravenous dosing is approximately 5 minutes, although maximum effect is not achieved for as long as 20 minutes due to the hysteresis (compartment) effect of a partially lipid soluble agent and the delayed penetration of the blood–brain barrier.
      • Coda B.
      • Tanaka A.
      • Jacobson R.C.
      • et al.
      Hydromorphone analgesia after intravenous bolus administration.
      Because it is more fat soluble than morphine, its onset of action is correspondingly faster than that of morphine, but is slower than highly lipid soluble drugs such as fentanyl. Hydromorphone can be prepared in highly concentrated solutions (up to 100 mg/mL) and because of the smaller volumes, can be easier to administer as a subcutaneous infusion than morphine in the setting of very high dose opioid administration, such as in opioid-resistant cancer pain.
      • Fudin J.
      • Smith H.S.
      • Toledo-Binette C.S.
      • et al.
      Use of continuous ambulatory infusions of concentrated subcutaneous (s.q.) hydromorphone versus intravenous (i.v.) morphine: cost implications for palliative care.
      However, hydromorphone administered subcutaneously in high concentrations can result in a painful local reaction,
      • Adams F.
      • Cruz L.
      • Deachman M.J.
      • Zamora E.
      Focal subdermal toxicity with subcutaneous opioid infusion in patients with cancer pain.
      although many patients do not experience this toxicity.
      • Bruera E.
      • MacEachern T.
      • Macmillan K.
      • et al.
      Local tolerance to subcutaneous infusions of high concentrations of hydromorphone: a prospective study.

      Spinal

      Hydromorphone can be given via the epidural route. The epidural to parenteral equianalgesic ratio is approximately 1:2.
      • Halpern S.H.
      • Arellano R.
      • Preston R.
      • et al.
      Epidural morphine vs hydromorphone in post-caesarean section patients.
      Duration of action after a single epidural dose of hydromorphone has been estimated between 7.7 and 19.3 hours.
      • Chestnut D.H.
      • Choi W.W.
      • Isbell T.J.
      Epidural hydromorphone for postcesarean analgesia.
      • Shulman M.S.
      • Wakerlin G.
      • Yamaguchi L.
      • Brodsky J.B.
      Experience with epidural hydromorphone for post-thoracotomy pain relief.
      • Henderson S.K.
      • Matthew E.B.
      • Cohen H.
      • Avram M.J.
      Epidural hydromorphone: a double-blind comparison with intramuscular hydromorphone for postcesarean section analgesia.

      Hydromorphone Metabolites

      Although hydromorphone is chemically very similar to morphine, its minor structural differences have a significant impact on its metabolism.
      Morphine undergoes metabolism to its 3-glucuronide, which has no analgesic activity but has been found to have significant neuroexcitatory properties. However, other morphine metabolites, morphine-6-glucuronide and normorphine, do have analgesic activity. Morphine-6-glucuronide has been found to accumulate in the presence of renal failure and may cause respiratory depression and other side effects.
      • Osborne R.
      • Joel S.
      • Slevin M.
      Morphine intoxication in renal failure; the role of morphine-6-glucuronide.
      • Hasselstrom J.
      • Sawe J.
      Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations.
      • Hagen N.A.
      • Foley K.M.
      • Cerbone D.J.
      • et al.
      Chronic nausea and morphine-6-glucuronide.
      There are other metabolites present in smaller amounts, including morphine-3-sulfate.
      Although less well studied, hydromorphone does not appear to have a 6-glucuronide metabolite but instead is extensively metabolized to hydromorphone-3-glucuronide and dihydroisomorphine glucuronide. Unconjugated hydromorphone is also excreted and smaller amounts of other metabolites include unconjugated and conjugated dihydromorphine, unconjugated dihydroisomorphine, hydromorphone-3-sulfate, norhydromorphone, and nordihydroisomorphine.
      • Zheng M.
      • McErlane K.M.
      • Ong M.C.
      Hydromorphone metabolites: isolation and identification from pooled urine samples of a cancer patient.
      Hydromorphone-3-glucuronide is about 2.5 times as potent as morphine-3-glucuronide as a neuroexcitant. Animal studies evaluating the behavioral effects of intracerebroventricular hydromorphone-3-glucuronide in the rat found an array of behaviors consistent with a neuroexcitatory effect, including myoclonic jerks, wet dog shakes, tonic clonic convulsions, touch evoked agitation, and others.
      • Wright A.W.
      • Nocente M.L.
      • Smith M.T.
      Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation.
      • Wright A.W.
      • Mather L.E.
      • Smith M.T.
      Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide.
      These animal studies correspond with myoclonus, allodynia, or seizures described in patients who have high levels of hydromorphone-3-glucuronide and are analogous to the neuroexcitatory effects of the less potent morphine metabolite, morphine-3-glucuronide.
      • Smith M.T.
      Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
      • Hagen N.A.
      • Swanson R.
      Strychnine-like multi-focal myoclonus and seizures from extremely high dose opioids: treatment strategies.
      Clinically, high-dose hydromorphone administration in the presence of renal failure has been associated with nausea
      • Babul N.
      • Darke A.C.
      • Hagen N.
      Hydromorphone metabolite accumulation in renal failure.
      and delirium.
      • Fainsinger R.
      • Schoeller T.
      • Boiskin M.
      • Bruera E.
      Palliative care round: cognitive failure and coma after renal failure in a patient receiving captopril and hydromorphone.
      Both of these effects are postulated to be related to hydromorphone metabolites. With chronic dosing of oral hydromorphone, blood levels of hydromorphone-3-glucuronide are about 30 times higher than blood levels of the parent drug, and this ratio rises to 100-fold in the presence of even modest renal impairment.
      • Babul N.
      • Darke A.C.
      • Hagen N.
      Hydromorphone metabolite accumulation in renal failure.
      • Hagen N.
      • Thirlwell M.P.
      • Dhaliwal H.S.
      • et al.
      Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone.
      In conclusion, hydromorphone appears to have active metabolites that may be responsible for neuroexcitatory and other unwanted effects, but unlike morphine, hydromorphone does not appear to be metabolized into an analgesically active 6-glucuronide. Neuroexcitatory effects of opioids, including hydromorphone, can present with a report of increased pain. Any report of increased pain in the setting of confusion, myoclonus, or other features of opioid neurotoxicity should prompt the clinician to consider rotating to a different opioid.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability: the application of alternate opioid therapy.
      • Manfredi P.L.
      • Borsook D.
      • Chandler S.W.
      • Payne R.
      Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations.
      • Ashby M.A.
      • Martin P.
      • Jackson K.A.
      Opioid substitution to reduce adverse effects in cancer pain management.
      • Bruera E.
      • Pereira J.
      Recent developments in palliative cancer care.

      Pharmacodynamics: Acute Pain

      Hydromorphone's analgesic properties have been studied in postoperative pain, acute trauma pain, burn wound pain, biliary and ureteral colic, and oral mucositis pain. Both children and adults have been studied. Table 1 summarizes the evidence for the efficacy of hydromorphone in the acute pain setting based on randomized controlled trials, as summarized in a recent Cochrane Systematic Review of hydromorphone.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      Table 1Hydromorphone for Acute Pain
      Results
      Comparison DrugReferencePatients (n)Equianalgesic Ratio UsedPain ControlAdverse Effects
      Oral HM vs. placeboGoldberg 1965
      • Goldberg R.S.
      • Shuman F.I.
      Oral hydromorphone in trauma.
      30All patients using HM and 30% of placebo group had some pain relief.No significant difference.
      Jain 1989
      • Jain A.K.
      • McMahon F.G.
      • Reder R.
      • et al.
      A placebo-controlled study of an oral solution of 5 and 10 mg of hydromorphone hydrochloride in postoperative pain.
      61HM statistically superior to placebo.No significant difference.
      Epidural HM vs. placebo/ fentanyl/sufentanilParker 1985
      • Parker E.O.
      • Brookshire G.L.
      • Bartel S.J.
      • Menard R.G.
      • et al.
      Effects of epinephrine on epidural fentanyl, sufentanil, and hydromorphone for postoperative pain.
      21All patients except placebo group had pain relief with same onset.Respiratory depression (RR < 10/min) found in 1 F and 2 HM group.
      Duration of action 5× longer for HM.
      Epidural HM vs. morphine5 studies
      • Chaplan S.R.
      • Duncan S.R.
      • Brodsky J.B.
      • Brose W.G.
      Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison.
      • Goodarzi M.
      Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery.
      • Halpern S.H.
      • Arellano R.
      • Preston R.
      • et al.
      Epidural morphine vs hydromorphone in post-caesarean section patients.
      • Swica L.
      • Midgley J.
      • Nunn R.
      • et al.
      Patient controlled epidural analgesia with hydromorphone versus single dose epidural morphine for post-caesarian analgesia.
      • Drakeford M.K.
      • Pettine K.A.
      • Brookshire L.
      • Ebert F.
      Spinal narcotics for postoperative analgesia in total joint arthroplasty. A prospective study.
      278HM :M = 7:1–5:1No significant difference in pain relief.3 studies—no difference;
      2 studies—lower incidence of pruritis with HM.
      Parenteral (IV or IM) HM vs. morphineseveral studies
      • Manfredi P.L.
      • Borsook D.
      • Chandler S.W.
      • Payne R.
      Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations.
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      • Coda B.
      • Tanaka A.
      • Jacobson R.C.
      • et al.
      Hydromorphone analgesia after intravenous bolus administration.
      • Rapp S.E.
      • Egan K.J.
      • Ross B.K.
      • et al.
      A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia.
      • Collins J.J.
      • Geake J.
      • Grier H.E.
      • et al.
      Patient-controlled analgesia for mucositis pain in children: a three-period crossover study comparing morphine and hydromorphone.
      • Hanna C.
      • Mazuzan J.E.
      • Abajian J.
      An evaluation of dihydromorphinone in treating postoperative pain.
      • Mahler D.L.
      • Forrest Jr., W.H.
      Relative analgesic potencies of morphine and hydromorphone in postoperative pain.
      • Searle N.R.
      • Roy M.
      • Bergeron G.
      • et al.
      Hydromorphone patient-controlled analgesia (PCA) after coronary artery bypass surgery.
      467HM :M = 7:1–5:1No significant difference in pain relief except in one study where morphine superior in time to treatment failure.
      • Coda B.
      • Tanaka A.
      • Jacobson R.C.
      • et al.
      Hydromorphone analgesia after intravenous bolus administration.
      7 studies showed no difference;
      1 study—lower incidence nausea/pruritis but poorer cognitive function in HM group;
      1 study—lower side effects in morphine group.
      Intramuscular HM vs. diamorphineWallenstein 1990
      • Wallenstein S.L.
      • Houde R.W.
      • Portenoy R.
      • et al.
      Clinical analgesic assay of repeated and single doses of heroin and hydromorphone.
      208HM:diamorphine = 4.5–5.5:1No significant difference.No significant difference.
      HM vs. meperidine4 studies
      • Hanna C.
      • Mazuzan J.E.
      • Abajian J.
      An evaluation of dihydromorphinone in treating postoperative pain.
      • Jasani N.B.
      • O'Conner R.E.
      • Bouzoukis J.K.
      Comparison of hydromorphone and meperidine for ureteral colic.
      • Nasits B.J.
      Dental evaluation of hydromorphone (Dilaudid) for oral and maxillo-facial surgery.
      • Deutsch E.V.
      Postoperative analgesia with hydromorphone and meperidine: a double-blind comparison.
      346HM more effective.No significant difference.
      Oral HM vs. oral transmucosal fentanylSharar 1998
      • Sharar S.R.
      • Bratton S.L.
      • Carrougher G.J.
      • et al.
      A comparison of oral transmucosal fentanyl citrate and oral hydromorphone for inpatient pediatric burn wound care analgesia.
      14HM:fentanyl = 1:6Fentanyl had increased pain relief at 30 minutes but overall efficacy same.No significant difference.
      Epidural HM vs. bupivacaineChestnut 1986
      • Chestnut D.H.
      • Choi W.W.
      • Isbell T.J.
      Epidural hydromorphone for postcesarean analgesia.
      52HM more effective.No significant difference.
      HM (SC) vs. indomethacin (IV)Uden 1984
      • Uden P.
      • Starck C.J.
      • Berger T.
      Comparison of indomethacin and dihydromorphinone in acute biliary stone pain.
      30No significant difference.Longer duration of nausea and vertigo with HM.
      HM = hydromorphone; M = morphine; IV = intravenous; IM = intramuscular; SC = subcutaneous.
      There is good evidence to show that hydromorphone has analgesic equivalency to other opioids for acute pain.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      The equianalgesic ratio for parenteral morphine to parenteral hydromorphone is between 5:1–7:1
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      • Bruera E.
      • Pereira J.
      • Watanabe S.
      • et al.
      Opioid rotation in patients with cancer pain. A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine.
      • Dunbar P.J.
      • Chapman C.R.
      • Buckley F.P.
      • Gavrin J.R.
      Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA.
      • Rapp S.E.
      • Egan K.J.
      • Ross B.K.
      • et al.
      A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia.
      Some experts have suggested that hydromorphone has less pruritis and nausea than morphine,
      • Sarhill N.
      • Walsh D.
      • Nelson K.A.
      Hydromorphone: pharmacology and clinical applications in cancer patients.
      • Rapp S.E.
      • Egan K.J.
      • Ross B.K.
      • et al.
      A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia.
      but these reports, including two studies of epidural hydromorphone
      • Chaplan S.R.
      • Duncan S.R.
      • Brodsky J.B.
      • Brose W.G.
      Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison.
      • Goodarzi M.
      Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery.
      and one study of intravenous hydromorphone,
      • Rapp S.E.
      • Egan K.J.
      • Ross B.K.
      • et al.
      A multidimensional comparison of morphine and hydromorphone patient-controlled analgesia.
      stand in contrast to a broader body of literature that suggests the risk of toxicity is similar between hydromorphone and morphine.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      Further large studies comparing hydromorphone and morphine may be needed before the question of the comparative adverse effect profile can be settled.

      Pharmacodynamics: Cancer Pain

      The role of hydromorphone has been evaluated in the setting of cancer-related pain, in comparison to morphine, oxycodone, as well as in comparison to itself (a variety of routes and formulations).
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      • Bruera E.
      • Sloan P.
      • Mount B.
      • et al.
      A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group.
      • Hays H.
      • Hagen N.
      • Thirlwell M.
      • et al.
      Comparative clinical efficacy and safety of immediate-release and controlled-release hydromorphone for chronic severe cancer pain.
      • Moulin D.E.
      • Kreeft J.H.
      • Murray-Parsons N.
      • Bouquillon A.I.
      Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain.
      • Walsh D.
      Pharmacological management of cancer pain.
      • Miller M.G.
      • McCarthy N.
      • O'Boyle C.A.
      • Kearney M.
      Continuous subcutaneous infusion of morphine vs. hydromorphone: a controlled trial.
      • Moriarty M.
      • McDonald C.J.
      • Miller A.J.
      A randomized crossover comparison of controlled-release hydromorphone tablets with controlled-release morphine tablets in patients with cancer pain.
      • Hagen N.A.
      • Babul N.
      Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain.
      Table 2 summarizes the evidence for hydromorphone in the setting of chronic cancer pain based on randomized controlled trials as summarized by the Cochrane Systematic Review of hydromorphone.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      There is good evidence to support the use of hydromorphone as a pure opioid agonist for chronic cancer pain. These studies suggest it is equivalent to morphine in terms of analgesic efficacy and side effect profile.
      • Quigley C.
      Hydromorphone for acute and chronic pain.
      Table 2Hydromorphone for Chronic Cancer Pain
      Results
      Comparison DrugReferencePatients (n)Equianalgesic Ratio UsedPain ControlAdverse Effects
      Oral modified-release HM vs. modified-release morphineMoriarty 1999
      • Moriarty M.
      • McDonald C.J.
      • Miller A.J.
      A randomized crossover comparison of controlled-release hydromorphone tablets with controlled-release morphine tablets in patients with cancer pain.
      89HM:M = 7.5:1No significant difference.No significant difference.
      Intramuscular HM vs. morphineHoude 1986
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      48HM:M = 7.5:1HM shorter acting.No significant difference.
      Oral modified-release HM vs. modified-release oxycodoneHagen 1997
      • Hagen N.A.
      • Babul N.
      Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain.
      44No significant difference.No significant difference although 2 patients in HM group reported hallucinations.
      Oral hydromorphone (IR) vs. hydromorphone (MR)Bruera 1996
      • Bruera E.
      • Sloan P.
      • Mount B.
      • et al.
      A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group.
      Hays 1994
      • Hays H.
      • Hagen N.
      • Thirlwell M.
      • et al.
      Comparative clinical efficacy and safety of immediate-release and controlled-release hydromorphone for chronic severe cancer pain.
      144No significant difference.No significant difference.
      Subcutaneous HM infusion vs. intravenous HM infusionMoulin 1991
      • Moulin D.E.
      • Kreeft J.H.
      • Murray-Parsons N.
      • Bouquillon A.I.
      Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain.
      20No significant difference.No significant difference.
      Oral HM vs. intramuscular HMHoude 1986
      • Houde R.
      Clinical analgesic studies of hydromorphone.
      96IM:oral = 5:1No significant difference.More side effects with IM group.
      HM = hydromorphone; M = morphine; IR = immediate-release; MR = modified-release; IM = intramuscular; IV = intravenous.
      The equianalgesic dosage for hydromorphone and morphine in the treatment of chronic cancer-related pain has not been firmly settled, and nor has the dose conversion for parenteral and oral hydromorphone.

      Chronic Nonmalignant Pain

      There are no published controlled trials studying the effectiveness of hydromorphone in chronic nonmalignant pain. One repeated-dose, single treatment study has recently been published that included patients with chronic nonmalignant pain.
      • Palangio M.
      • Northfelt D.W.
      • Portenoy R.K.
      • et al.
      Dose conversion and titration with a novel, once-daily, OROS osmotic technology, extended-release hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain.
      In this study, patients were converted from their baseline opioid regimen to a novel once daily modified-release hydromorphone preparation. Out of the 445 patients in the study, 358 had chronic nonmalignant pain. Study participants found significant improvement in pain on the extended release hydromorphone and no change in side-effect profile compared to their previous opioid regimen.
      There is, however, extensive published information to suggest that opioids can be appropriate for chronic nonmalignant pain and there is no reason to suppose that hydromorphone would be different than morphine, oxycodone, fentanyl, or other opioids in this regard.

      Novel Preparations

      Modified-release opioids have been widely used for the long-term management of chronic pain. Modified-release formulations are considered to be more convenient for patients because they alleviate the need for 4- to 6-hourly dosing intervals, which are required with immediate-release preparations. Frequent dosing of opioids can be associated with poor compliance, resulting in poorer pain control and quality of life.
      • Walsh D.
      Pharmacological management of cancer pain.
      • Ferrell B.
      • Wisdom C.
      • Wenzl C.
      • Brown J.
      Effects of controlled-released morphine on quality of life for cancer pain.
      Clinical efficacy and safety
      • Bruera E.
      • Sloan P.
      • Mount B.
      • et al.
      A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group.
      • Hays H.
      • Hagen N.
      • Thirlwell M.
      • et al.
      Comparative clinical efficacy and safety of immediate-release and controlled-release hydromorphone for chronic severe cancer pain.
      as well as steady-state pharmacokinetics
      • Hagen N.
      • Thirlwell M.P.
      • Dhaliwal H.S.
      • et al.
      Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone.
      have been described for 12-hour modified-release hydromorphone in comparison with immediate-release hydromorphone in patients with chronic severe cancer pain, and the clinical efficacy and safety of a 12-hour modified-release hydromorphone product has been compared to a modified-release oxycodone formulation.
      • Hagen N.A.
      • Babul N.
      Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain.
      Twice-daily use of the latter hydromorphone preparation is available in many countries, but is not currently available in the United States.
      There are two once-daily hydromorphone preparations that have been recently described. The drug delivery vehicle is quite different between these two preparations, although the pharmacodynamics and clinical outcome of the two appear to be similar.
      The OROS preparation of once-a-day hydromorphone is an osmotic technology extended-release hydromorphone formulation. It consists of an osmotically active bi-layer core enclosed within a semi-permeable tablet shell membrane. In the gastrointestinal tract, water flows across the surrounding membrane at a predictable rate, causing the push layer to expand the drug going into suspension. The drug is then slowly forced through the orifice of the tablet because of the pressure from the expanding push layer. The tablet releases drug independent of the ambient pH or GI motility. This technology has been evaluated in the delivery of several other medications, including albuterol, glipizide, isradipine, nifedipine, verapamil, oxybutynin, and methylphenidate. The pharmacokinetics of hydromorphone absorption with the OROS vehicle have been characterized.
      • Shah J.G.
      • Singh S.
      • Peng J.
      Multiple dose pharmacokinetics of OROS and immediate release (IR) hydromorphone (HM) in healthy subjects.
      • Drover D.R.
      • Angst M.S.
      • Valle M.
      • Ramaswamy B.
      • et al.
      Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers.
      • Angst M.S.
      • Drover D.R.
      • Lotsch J.
      • et al.
      Pharmacodynamics of orally administered sustained-release hydromorphone in humans.
      The conversion from other opioids to OROS extended-release hydromorphone was described in a large number of patients with both cancer and non-cancer pain.
      • Palangio M.
      • Northfelt D.W.
      • Portenoy R.K.
      • et al.
      Dose conversion and titration with a novel, once-daily, OROS osmotic technology, extended-release hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain.
      This was an open label, repeated dose, single treatment, uncontrolled, multicenter study of patients with either cancer or non cancer pain, who were previously on a different opioid. The dose of the original opioid was stabilized, patients were converted to the OROS product, dose adjustments were made approximately every 2–3 days and the dose was titrated to effect. On average it took about twelve days to switch from the previous opioid to the OROS hydromorphone extended-release preparation. Patients in general had good control of pain and the product was well tolerated.
      Palladone is a second once-a-day hydromorphone product that is quite different in its design in comparison to OROS. This product is a modified-release capsule preparation that can be administered by sprinkling on food or through a feeding tube if necessary. Single dose studies suggest a rapid initial peak blood level at about 2 hours and a second, broad, slow peak at about 18–24 hours (Figure 1). Steady-state is achieved in about three days. Palladone has been extensively studied, in seven clinical phase 1 trials and seven phase 2/3 clinical trials. These studies involved patients with pain from both malignant and nonmalignant causes, including patients with osteoarthritis, post-surgical pain, and cancer, and there has been longitudinal observation of patients receiving the preparation chronically.
      • Kremer A.
      It has been found to have an analgesic effect, side-effect, and safety profile similar to immediate-release hydromorphone. As would be anticipated, steady-state comparison of pharmacokinetics of Palladone once-daily to every-6-hour immediate-release hydromorphone resulted in similar bioavailability over 24 hours but significantly reduced fluctuation in dosing for the once-daily product.

      Woodson ME, Strambaugh JE, Lacouture, PG, et al. Assessment of once-a-day controlled-release hydromorphone (Palladone XL) with 7 days' treatment at stable doses. Poster presented at the Annual Meeting of the American College of Clinical Pharmacology; Kansas City, October 24–27, 1999.

      Figure thumbnail gr1
      Figure 1Single-dose pharmacokinetics of Palladone (hydromorphone extended-release) capsules. (Reproduced with permission from Purdue Pharma US.)
      The nomenclature of the 12-hour and 24-hour products varies from country to country. A 12-hour modified-release hydromorphone product has been marketed under the trade name Hydromorph Contin in Canada and as Palladone SR in Britain and Germany. Palladone XL is the novel once-daily preparation approved in Canada. It is under review in the United States, where it will be marketed under the trade name Palladone, and also in Australia and other countries. Once-daily Palladone marks the first modified-release hydromorphone preparation in the U.S.
      Both OROS and once-daily Palladone are appropriate for control of chronic pain and have a more convenient once-daily dosing regimen compared with immediate-release hydromorphone.

      Hydromorphone and Prescription Opioid Analgesic Abuse

      There is a long history of concern that medical exposure of a patient to an opioid can result in addiction. However, there is evidence to suggest that the perceived risk of iatrogenic addiction is vastly greater than the actual risk. Whereas the risk of subsequent addiction varies depending on several patient-related, disease-related, and other characteristics, one report identified that approximately 4 in 10,000 patients exposed to an opioid for medical reasons developed iatrogenic addiction
      • Porter J.
      • Jick H.
      Addiction rare in patients treated with narcotics.
      and other publications confirm the risk to be very low.
      • Portenoy R.K.
      Chronic opioid therapy in nonmalignant pain.
      • Perry S.
      • Heidrich G.
      Management of pain during debridement: a survey of U.S. burn units.
      • Darke A.C.
      • Stewart J.H.
      Efficacy and abuse potential of opioid analgesics and the treatment of chronic noncancer pain.
      Further, the extent to which prescription opioid analgesics contribute to the national drug abuse problem appears to be considerably less than one might anticipate. The drug-abuse warning network (DAWN) is a program sponsored by the Substance Abuse and Mental Health Services Administration and the U.S. Department of Health and Human Services. This program monitors national drug abuse trends through retrospective audits of medical records from the emergency rooms of approximately 500 hospitals across the United States. It captures and codes the non-medical use of a substance for its psychic effect, dependence, or suicide attempt or gesture. A landmark article by David Joranson and colleagues
      • Joranson D.E.
      • Ryan K.M.
      • Gilson A.M.
      • Dahl J.L.
      Trends in medical use and abuse of opioid analgesics.
      compared the reports of emergency department admissions resulting from drug abuse as identified by DAWN, with the legitimate medical use of opioids in the general population (measured in grams and grams per 100,000 population) from the period 1990–1996. The use of specific prescription opioid analgesics for medical purposes was compared to the number of actual episodes of each of these analgesics being reported in the emergency rooms under survey.
      From 1990–1996, legitimate medical use of opioids in the United States increased considerably: morphine use increased by 59%, oxycodone by 23%, and hydromorphone by 19%. During the same period, the number of episodes of drug abuse increased significantly in the United States, reflected by an increase from 650,460 to 907,561 mentions among the 500 emergency rooms that were part of the DAWN survey. Most of the increase identified by emergency rooms was related to illicit drug abuse such as cocaine. During this same period the total absolute number of drug abuse mentions per year due to opioid analgesics increased slightly; however, the proportion of drug abuse episodes for opioid analgesics fell considerably compared with illicit drugs. During a time in which the DAWN survey system found that illicit drug use prompting emergency room visits rose by 109%, reports of ER visits related to abuse for morphine increased only slightly (3%), and decreased significantly for oxycodone (−29%) and for hydromorphone (−15%). The authors concluded: “The trend of increasing medical use of opioid analgesics to treat pain does not appear to contribute to increases in the health consequences of opioid analgesic abuse.”
      • Joranson D.E.
      • Ryan K.M.
      • Gilson A.M.
      • Dahl J.L.
      Trends in medical use and abuse of opioid analgesics.
      An important recent article challenged these observations.
      • Gilson A.M.
      • Ryan K.M.
      • Joranson D.E.
      • Dahl J.L.
      A reassessment of trends in the medial use and abuse of opioid analgesics and implications for diversion control: 1997–2002.
      Comparing amounts of opioids legitimately distributed to the retail level with data from the DAWN survey system from 1997–2002 paints a very different picture compared with data from 1991–1996. In 2002, opioid analgesics accounted for 9.85% of all drug abuse, up from 5.75% in 1997. An increase in medical use of almost all opioid analgesics was associated with a proportionate increase in opioid abuse. However, the greatest proportion of increase in abuse during that time was related to alcohol and illicit drugs.
      Thus, the overall contribution of opioid analgesics to the national drug problem appears low. At a time that prescription of opioid analgesics increased greatly in the United States, the actual incidents of specific opioids being diverted increased proportionately. However, determinants of opioid abuse within society are complex and it is not the case that opioid abuse is closely linked to legitimate medical use in specific patients. Further, illicit drug abuse such as cocaine and heroin is of such magnitude that the diversion of opioids intended for medical use is small in comparison. Addressing diversion while maintaining balance to assure availability of opioids for legitimate medical use remains a topic of intense interest.
      • Gilson A.M.
      • Ryan K.M.
      • Joranson D.E.
      • Dahl J.L.
      A reassessment of trends in the medial use and abuse of opioid analgesics and implications for diversion control: 1997–2002.
      There is no evidence that hydromorphone is intrinsically more abusable or that it is materially different from its cousins, such as morphine and other pure opioid agonists. The strong consensus of regulatory agencies, experts in pain management and professional organizations is that chronic administration of opioids for malignant or nonmalignant pain is a safe and legitimate medical practice when undertaken as part of a comprehensive pain assessment and management approach.

      Summary

      There is good evidence to support the use of hydromorphone in both the acute pain setting and the setting of chronic cancer pain. Hydromorphone appears to have similar analgesic properties to morphine and a similar side effect profile. Hydromorphone has become a popular choice for the treatment of cancer-related pain in the U.S., Canada, and Great Britain. Despite the extensive clinical use, the following controversies about hydromorphone continue to exist:
      • Equianalgesic ratios. What is the clinically appropriate equianalgesic ratio between hydromorphone and morphine? What is the equianalgesic ratio between oral and intravenous hydromorphone?
      • Adverse effects. A handful of studies from the acute pain literature suggest that hydromorphone may have a more favorable side-effect profile than morphine, but other studies do not support this stance.
      There are very few published studies on the role of hydromorphone in the setting of chronic nonmalignant pain, and further research is needed in this area.
      The role of hydromorphone metabolites in the relief of pain and in the development of toxicity remains an area of ongoing study. The relative contribution of concurrent liver or renal impairment remains uncertain.

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