Routine drug monitoring of serum concentrations of morphine,morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients

Abstract

The clinical importance of routine drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. We measured morphine, M6G and M3G serum concentrations in cancer pain patients receiving oral (n = 263, median dose 80 mg/24 hours) or subcutaneous (sc) (n = 35, median dose 110 mg/24 hours) morphine. Regression analyses were performed to investigate if serum concentrations of morphine, M3G and M6G predicted pain intensity (Brief Pain Inventory), health-related quality-of-life variables (EORTC QLQ-C30) and cognitive function (Mini-Mental Score). Serum concentrations were also compared in patients categorized as morphine ’treatment successesfland ‘treatment failures’.

We observed that serum concentrations of morphine, M6G or M3G did not predict pain intensity, cognitive function, nausea or tiredness. ‘Treatment failuresflcaused by nausea, tiredness, cognitive failure or constipation did not have statistically significant different morphine, M6G and M3G serum concentrations than patients classified as ’treatment successes’.

In conclusion, this study did not observe any concentration–effect relationships of morphine, M3G or M6G with pain intensity, nausea, constipation, tiredness or cognitive failure in blood samples obtained during routine clinical drug monitoring in cancer patients. This result suggests that therapeutic drug monitoring as a routine tool during chronic morphine treatment has limited value for clinical decision making.

Keywords

cancer drug monitoring morphine morphine-3-glucuronide morphine-6-glucuronide

Get full access to this article

View all access options for this article.

References

Glare PA , Walsh TD . Clinical pharmacokinetics of morphine. Ther Drug Monit 1991; 13: 1–23.

Wollf T , Samuelsson H , Hedner T . Morphine and morphine metabolite concentrations in cerebrospinal fluid and plasma in cancer pain patients after slow-release oral morphine administration. Pain 1995; 62: 147–154.

Paul D , Standifer KM , Inturrisi CE , Pasternak GW . Pharmacological characterization of morphine-6-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251: 477–483.

Portenoy RK , Thaler HT , Inturrisi CE , Friedlander-Klar H , Foley KM . The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther 1992; 51: 422–431.

Faura CC , Moore A , Horga JF , Hand CW , McQuay HJ . Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain. J Pain Symptom Manage 1996; 11: 95–102.

Klepstad P , Kaasa S , Borchgrevink PC . Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol 2000; 55: 713–719.

Bodd E , Jacobsen D , Lund E , Ripel A , Morland J , Wiik Larsen E . Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Hum Exp Toxicol 1990; 9: 317–321.

Tiseo P , Thaler HT , Lapin J , Inturrisi CE , Portenoy RK , Foley KM . Morphine-6-glucuronide concentrations and opioid-related side effects: a survey in cancer patients. Pain 1995; 61: 47–54.

Faura CC , Olaso MJ , Cabanes CG , Horga JF . Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved? Pain 1996; 65: 25–30.

10.

Sjøgren P , Thunedborg LP , Christrup L , Hansen SH , Franks J . Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case stories. Acta Anaesthesiol Scand 1998; 42: 1070–1075.

11.

Goucke, CR , Hackett, P , Ilett, K . Concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide in serum and cerebrospinal fluid following morphine administration to patients with morphine-resistant pain. Pain 1994; 56: 145–149.

12.

Penson RT , Joel SP , Bakhshi K , Clark SJ , Langford RM , Slevin ML . Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharm Ther 2000; 68: 667–676.

13.

Faura CC , Collins SL , Moore A , McQuay HJ . Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain 1998; 74: 43–53.

14.

Klepstad P , Dale O , Kaasa S , et al. Influences on serum concentration of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 2003; 47: 725–731.

15.

Aaronson NK , Ahmedzai S , Bergman B , et al. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376.

16.

Fayers P , Aaronson NK , Bjordal K , Sullivan M . EORTC QLQ-C30 scoring manual. Brussels: EORTC Study Group on Quality of Life, 1995.

17.

Daut RL , Cleeland CS , Flanery RC . Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain 1983; 17: 197–210.

18.

Klepstad P , Loge JH , Borchgrevink PC , Mendoza TR , Cleeland CS , Kaasa S . The Norwegian Brief Pain Inventory questionnaire: translation and validation in cancer pain patients. J Pain Symptom Manage 2002; 24: 517–525.

19.

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.

20.

Folstein MF , Folstein SE , McHugh PR . ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

21.

Pereira J , Hanson J , Bruera E . The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997; 79: 835–842.

22.

Karnofsky DA , Abelmann WH , Craver LF , Burchenal JH . The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948; 1: 634–656.

23.

Bogusz MJ , Maier R-D , Driessen S . Morphine, morphine-3-glucuronide, morphine-6-glucuronide, and 6-monoacetylmorphien determined by means of atmospheric pressure chemical ionization-mass-spectrometry-liquid cromatography in body fluids of heroin victims. J Anal Toxicol 1997; 21: 346–355.

24.

Serlin RC , Mendoza TR , Nakamura Y , Edwards KR , Cleeland CS . When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 1995; 61: 277–284.

25.

Radbruch L , Loick G , Schulzeck S , et al. Intravenous titration with morphine for severe cancer pain: report of 28 cases. Clin J Pain 1999; 15: 173–178.

26.

Cull A , Hay C , Love SB , Mackie M , Smets E , Stewart M . What do cancer patients mean when they complain of concentration and memory problems. Br J Cancer 1996; 74: 1674–1679.

27.

Fayers P , Machin D . Sample size: how many patients are necessary. Br J Cancer 1995; 72: 1–9.

28.

Somogyi A , Nation RL , Olweny C , et al. Plasma concentrations and renal clearance of morphine, morphine-3-glucuronide and morphine-6-glucuronide in cancer patients receiving morphine. Clin Pharmacokin 1993; 24: 413–420.

29.

Mercadante S . The role of morphine glucuronides in cancer pain. Palliat Med 1999; 13: 95–104.

30.

Wollf T , Samuelsson H , Hedner T . Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients. Pain 1996; 68: 209–216.

31.

Gong Q-L , Hedner J , Bjorkman R , Hedner T . Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 1992; 48: 249–255.

32.

Smith MT , Wright AW , Williams BE , Stuart G , Cramond T . Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain. Anesth Analg 1999; 88: 109–116.

33.

Hagen NA , Foley KM , Cerbone DJ , Porteneoy RK , Inturrisi CE . Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage 1991; 6: 125–128.

34.

Ashby MA , Fleming BG , Wood MJ , Somogyi A . Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage 1997; 14: 157–167.

35.

Wood MM , Ashby MA , Somogyi A , Fleming BG . Neuropsychological and pharmacokinetic assessment of hospice inpatients receiving morphine. J Pain Symptom Manage 1998; 16: 112–120.

36.

Moore A , Gavaghan D , Tramer MR , Collins SL , McQuay HJ . Size is everything-large amounts of information are needed to overcome random effects in estimation direction and magnitude of treatment effects. Pain 1998; 78: 209–216.

37.

Thompson, SJ , Koszdin K , Bernards CM . Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000; 92: 1392–1399.

38.

Amanzio M , Pollo A , Maggi G , Benedetti F . Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 2001; 90: 205–215.

39.

Crain SM , Shen K-F . Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 gang-lioside-regulated opioid receptor functions. TiPS 1998; 19: 358–365.

40.

Barjavel MJ , Scherrman J-M , Bhargava HN . Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study. Br J Pharmacol 1995; 116: 3205–3210.

41.

Weiss SC , Emanuel LL , Fairclough DL , Emanuel EJ . Understanding the experience of pain in the terminally ill patients. Lancet 2001; 357: 1311–1315.

42.

Mazzocato C , Sweeney C , Bruera E . Clinical research in palliative care: patient populations, symptoms, interventions and endpoints. Palliat Med 2001; 15: 163–168.