title: Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain.
abstract: BACKGROUND
  Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration.
  
  
  METHODS
  The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale <4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay.
  
  
  RESULTS
  Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L·h(-1)·kg(-1); the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively).
  
  
  CONCLUSIONS
  This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.
authors.affiliation: †SIMPAR (Study In Multidisciplinary PAin Research) group, Unit of Clinical Pharmacokinetics in Transplantation and Autoimmune Disease, and Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, and Department of Genetics and Microbiology, and Department of Experimental and Applied Pharmacology, University of Pavia; ‡Fondazione IRCCS Policlinico S. Matteo: Pain Therapy Service; §Fondazione IRCCS Policlinico S. Matteo; Departments of ¶Genetics and Microbiology II: Department of Experimental and Applied Pharmacology, ‖Drug Sciences, Pharmacology Section; and **Surgical, Clinical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Gregori
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Minella
authors.forename: Manuela
authors.initials: M
authors.lastname: De Gregori
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.forename: Guglielmina N
authors.initials: GN
authors.lastname: Ranzani
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegri
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D059350:Chronic Pain / Q000188:drug therapy* / Q000209:etiology; D016903:Drug Monitoring; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D009022:Morphine Derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D009369:Neoplasms / Q000150:complications / Q000378:metabolism; D010147:Pain Measurement; D011110:Polymorphism, Genetic; D012737:Sex Factors; D053719:Tandem Mass Spectrometry
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide