Open Access Open Access  Restricted Access Subscription or Fee Access

Pain management in chronic kidney disease: The pharmacokinetics and pharmacodynamics of hydromorphone and hydromorphone-3-glucuronide in hemodialysis patients

Sara N. Davison, MD, MHSc (bioethics), FRCP(C), Patrick R. Mayo, PhD, SFO


Objective: To describe the pharmacokinetics of hydromorphone (HM) and its primary metabolite hydromorphone- 3-glucuronide (H3G) both on and off dialysis in relation to the pharmacodynamic measurements of pain.
Design: Prospective, open-label, observational study.
Setting: Canadian, university-based renal program.
Participants: Twelve anuric hemodialysis patients with chronic pain, established on immediate-release HM.
Main Outcome Measures: HM and H3G plasma concentrations were measured during and between hemodialysis treatments using a reverse-phase highperformance liquid chromatography assay with liquid chromatography/mass spectrometer/mass spectrometer detection. The McGill Pain Questionnaire (MPQ) and a Visual Analogue Scale (VAS) were used to measure pain. Noncompartmental analyses were conducted. Adverse effects were recorded.
Results: HM did not substantially accumulate (accumulation factor R = 2.7 (1.6)), most likely due to the rapid conversion to H3G. Conversely, H3G accumulated between dialysis treatments (R = 12.5 (12.1)) but appeared to be effectively removed during hemodialysis (1.8 (0.7), p = 0.03). HM resulted in >65 percent reduction in pain over dosing intervals. Mean MPQ pain scores decreased from 39.8 (18.2) to 12.3 (16.2) on dialysis and from 35.0 (18.5) to 15.5 (13.6) between dialysis treatments. Mean VAS pain scores decreased from 7.5 (2.5) to 3.0 (1.5) on dialysis and from 5.9 (3.2) to 4.4 (1.6) between dialysis treatments. No clinically significant opioid toxicity was observed. The accumulation of H3G between hemodialysis treatments was associated with greater sensory-type pain (r = 0.76, p < 0.0001) and reduced duration of analgesia.
Conclusions: HM may be a safe and effective opioid for use in selected hemodialysis patients.


kidney failure, dialysis, opioids, hydromorphone, hydromorphone-3-glucuronide, pharmacokinetics, pharmacodynamics, chronic pain

Full Text:



Davison SN: Pain in hemodialysis patients: Prevalence, cause, severity, and management. Am J Kidney Dis. 2003; 42: 1239-1247.

Davison SN, Jhangri GS, Johnson JA: Cross-sectional validity of a modified Edmonton symptom assessment system in dialysis patients: A simple assessment of symptom burden. Kidney Int. 2006; 69: 1621-1625.

Davison SN, Jhangri GS, Johnson JA: Longitudinal validation of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients. Nephrol Dial Transplant. 2006; 21: 3189-3195.

Canadian Institute for Health Information: Canadian organ replacement registry: Dialysis and renal transplantation. Ottawa, ON, 2002.

US Renal Data System, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases: US Renal Data System; USRDS 2004. 2004 Annual data report: Atlas of end-stage renal disease in the United States, Bethesda, MD, 2004.

McQuay H, Moore A: An Evidence Based Resource for Pain Relief. Oxford: Oxford University Press, 1998.

Pergolizzi J, Boger RH, Budd K, et al.: Opioids and the management of chronic severe pain in the elderly: Consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone). Pain Pract. 2008; 8(4): 287-313.

Bailie GR, Mason NA, Bragg-Gresham JL, et al.: Analgesic prescription patterns among hemodialysis patients in the DOPPS: Potential for under prescription. Kidney Int. 2004; 65: 2419-2425.

Lee MA, Leng ME, Tiernan EJ: Retrospective study of the use of hydromorphone in palliative care patients with normal and abnormal urea and creatinine. Palliative Med. 2001; 15: 26-34.

Chen YL, Hanson GD, Jiang X, et al.: Simultaneous determination of hydrocodone and hydromorphone in human plasma by liquid chromatography with tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 769: 55-64.

Somers D, Basa L, Impey G, et al.: Simultaneous qualitative and quantitative LC/MS/MS analysis of opiates in biological matrices. Poster number: TH-134, 2003.

Melzack R: The McGill pain questionnaire: Major properties and scoring methods. Pain. 1975; 1: 277-299.

Caraceni A, Cherny N, Fainsinger R, et al.: Pain measurement tools and methods in clinical research in Palliative Care: Recommendations of an expert working group of the European Association of Palliative Care. J Pain Symptom Manage. 2002; 23: 239-255.

Littman GS, Walker BR, Schneider BE: Reassessment of verbal and visual analogue ratings in analgesic studies. Clin Pharmacol Ther. 1985; 38: 16-23.

Chauvin M, Sandouk P, Scherrmann JM, et al.: Morphine pharmacokinetics in renal failure. Anesthesiology. 1987; 66: 327-331.

Jamal JA, Joh J, Bastani B: Removal of morphine with the new high-efficiency and high-flux membranes during haemofiltration and haemodialfiltration. Nephrol Dial Transplant. 1998; 13: 1535-1537.

Hagen NA, Foley KM, Cerbone DJ, et al.: Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage. 1991; 6: 125-128.

Osborne R, Joel S, Grebenik K, et al.: The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther. 1993; 54: 158-167.

Sear JW, Hand CW, Moore RA, et al.: Studies on morphine disposition: Influence of renal failure on kinetics of morphine and its metabolites. Br J Anaesth. 1989; 62: 28-32.

Hanna MH, D’Costa F, Peat SJ, et al.: Morphine-6-glucuronide disposition in renal impairment. Br J Anaesth. 1993; 70: 511-514.

Osborne RJ, Joel SP, Trew D, et al.: The analgesic activity of morhine-6-glucuronide. Lancet. 1988; 1: 828.

Osborne RJ, Joel SP, Trew D, et al.: Morphine and metabolite behaviour and different routes of morphine administration: demonstration of the active metabolite morphine-6-glucuronide. Clin Pharmacol Therapeut. 1990; 47: 12-19.

Portenoy RK: Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage. 1990; 5: S46-S62.

Portenoy RK, Khan E, Layman M, et al.: Chronic morphine therapy for pain for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations. Neurology. 1991; 41: 1457-1461.

Davison SN: Chronic pain in end-stage renal disease. Adv Chronic Kidney Dis. 2005; 12: 326-334.

Murray A, Hagen NA: Hydromorphone. J Pain Symptom Manage. 2005; 29: S57-S66

Bruera E, Sloan P, Mount B, et al.: A randomized, doubleblind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-releae hydromorphone with immediaterelease hydromorphone in patients with cancer pain. J Clin Oncol. 1996; 14: 1713-1717.

Dunbar PJ, Chapman CR, Buckley FP, et al.: Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA. Pain. 1996; 68: 265-270.

Valner JJ, Stewart JT, Kotzan JA, et al.: Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol. 1981; 21: 152-156.

Quigley C: Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev CD003447, 2002.

Vallner JJ, Stewart JT, Kotzan JA, et al.: Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects. J Clin Pharmacol. 1981; 21: 152-156.

Zheng M, McErlane KM, Ong MC: Hydromorphone metabolites: isolation and identification from pooled urine samples of a cancer patient. Xenobiotica. 2002; 32: 427-439.

Hagen N, Thirlwell MP, Dhaliwal HS, et al.: Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlledrelease hydromorphone. J Clin Pharmacol. 1995; 35: 37-44.

Durnin C, Hind ID, Wickens MM, et al.: Pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR) in subjects with renal impairment. Proc West Pharmacol Soc. 2001; 44: 81-82.

Babul N, Darke AC, Hagen N: Hydromorphone metabolite accumulation in renal failure. J Pain Symptom Manage. 1995; 10: 184-186.

Wright AWE, Nocente ML, Smith MT: Hydromorphone-3-glucuronide: Biochemical synthesis and preliminary pharmacological evaluation. Life Sci. 1993; 63: 401-411.

Wright AW, Mather LE, Smith MT: Hydromorphone-3-glucuronide: A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide. Life Sci. 2001; 69: 409-420.

Smith GD, Smith MT: Morphine-3-glucuronide: Evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat. Pain. 1995; 62: 51-60.

Hagen N, Swanson R: Mutifocal myoclonus and seizures in extemely high dose opioid administration. Proceedings of the American Academy of Neurology in New York, New York, 1993.

Osborne RJ, Joel SP, Slevin ML: Morphine intoxication in renal failure: The role of morphine-6-glucuronide. Br Med J (Clin Res Ed). 1986; 292: 1548-1549.

Penson RT, Joel SP, Gloyne A, et al.: Morphine analgesia in cancer pain: Role of the glucuronides. J Opioid Manag. 2005; 1: 83-90.



  • There are currently no refbacks.