• 1
    International Narcotics Control Board. Narcotic Drugs [online]. Available at (last accessed 29 May 2012).
  • 2
    Dale O, Moksnes K, Kaasa S. European Palliative Care Research Collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat Med 2011; 25: 494503.
  • 3
    Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan MI, Fishbain DA, Foley KM, Fudin J, Gilson AM, Kelter A, Mauskop A, O'Connor PG, Passik SD, Pasternak GW, Portenoy RK, Rich BA, Roberts RG, Todd KH, Miaskowski C. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009; 10: 11330.
  • 4
    Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, Dale O, De Conno F, Fallon M, Hanna M, Haugen DF, Juhl G, King S, Klepstad P, Laugsand EA, Maltoni M, Mercadante S, Nabal M, Pigni A, Radbruch L, Reid C, Sjogren P, Stone PC, Tassinari D, Zeppetella G. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012; 13: e5868.
  • 5
    Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv 2009; 60: 143945.
  • 6
    Christrup LL, Foster D, Popper LD, Troen T, Upton R. Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: a randomized, double-blind, double-dummy, two-way, crossover study. Clin Ther 2008; 30: 46981.
  • 7
    Joshi GP. Sufentanil for chronic pain management. Fut Neurol 2010; 5: 7916.
  • 8
    Strain EC, Walsh SL, Preston KL, Liebson IA, Bigelow GE. The effects of buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl) 1997; 129: 32938.
  • 9
    Poklis A. Fentanyl: a review for clinical and analytical toxicologists. J Toxicol Clin Toxicol 1995; 33: 43947.
  • 10
    Streisand JB, Varvel JR, Stanski DR, Le ML, Ashburn MA, Hague BI, Tarver SD, Stanley TH. Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991; 75: 2239.
  • 11
    Kharasch ED, Hoffer C, Altuntas TG, Whittington D. Quinidine as a probe for the role of p-glycoprotein in the intestinal absorption and clinical effects of fentanyl. J Clin Pharmacol 2004; 44: 22433.
  • 12
    Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007; 81: 42944.
  • 13
    Tzvetkov MV, Saadatmand AR, Lotsch J, Tegeder I, Stingl JC, Brockmoller J. Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther 2011; 90: 14350.
  • 14
    Thorn M, Finnstrom N, Lundgren S, Rane A, Loof L. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 2005; 60: 5460.
  • 15
    Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol 2011; 201: 10567.
  • 16
    Wandel C, Kim R, Wood M, Wood A. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 2002; 96: 91320.
  • 17
    Rodriguez M, Ortega I, Soengas I, Suarez E, Lukas JC, Calvo R. Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat. J Pharm Pharmacol 2004; 56: 36774.
  • 18
    Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH. Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther 2007; 81: 53946.
  • 19
    Bostrom E, Simonsson US, Hammarlund-Udenaes M. Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci 2005; 94: 10606.
  • 20
    Bostrom E, Simonsson US, Hammarlund-Udenaes M. In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab Dispos 2006; 34: 162431.
  • 21
    Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011; 11: 27486.
  • 22
    Guitton J, Buronfosse T, Desage M, Lepape A, Brazier JL, Beaune P. Possible involvement of multiple cytochrome P450s in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol 1997; 53: 16139.
  • 23
    Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25: 107280.
  • 24
    Dayer P, Desmeules J, Leemann T, Striberni R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem Biophys Res Commun 1988; 152: 4116.
  • 25
    Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004; 32: 44754.
  • 26
    Mikus G, Weiss J. Influence of CYP2D6 genetics on opioid, kinetics, metabolism and response. Curr Pharmacogen 2005; 3: 4352.
  • 27
    Kirchheiner J, Schmidt H, Tzvetkov M, Keulen JT, Lotsch J, Roots I, Brockmoller J. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007; 7: 25765.
  • 28
    Madadi P, Ross CJ, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, Koren G. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther 2009; 85: 315.
  • 29
    Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010; 160: 91930.
  • 30
    Andreassen TN, Eftedal I, Klepstad P, Davies A, Bjordal K, Lundstrom S, Kaasa S, Dale O. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study. Eur J Clin Pharmacol 2012; 68: 5564.
  • 31
    Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29: 114655.
  • 32
    Lotsch J, Skarke C, Schmidt H, Rohrbacher M, Hofmann U, Schwab M, Geisslinger G. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin Pharmacol Ther 2006; 79: 3548.
  • 33
    Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 2004; 100: 12033.
  • 34
    Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, Miners JO. Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 2000; 10: 67985.
  • 35
    Coffman BL, King CD, Rios GR, Tephly TR. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y268 and UGT2B7H268. Drug Metab Dispos 1998; 26: 737.
  • 36
    Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, Kaasa S, Krokan HE, Skorpen F. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002; 58: 3536.
  • 37
    Holthe M, Rakvag TN, Klepstad P, Idle JR, Kaasa S, Krokan HE, Skorpen F. Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 2003; 3: 1726.
  • 38
    Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003; 73: 56674.
  • 39
    Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004; 16: 3644.
  • 40
    Galvan A, Skorpen F, Klepstad P, Knudsen AK, Fladvad T, Falvella FS, Pigni A, Brunelli C, Caraceni A, Kaasa S, Dragani TA. Multiple loci modulate opioid therapy response for cancer pain. Clin Cancer Res 2011; 17: 45817.
  • 41
    Klepstad P, Fladvad T, Skorpen F, Bjordal K, Caraceni A, Dale O, Davies A, Kloke M, Lundstrom S, Maltoni M, Radbruch L, Sabatowski R, Sigurdardottir V, Strasser F, Fayers PM, Kaasa S. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 2011; 152: 113945.
  • 42
    Laugsand EA, Fladvad T, Skorpen F, Maltoni M, Kaasa S, Fayers P, Klepstad P. Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids. Eur J Cancer 2011; 47: 168291.
  • 43
    Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54: 15867.
  • 44
    Coller JK, Christrup LL, Somogyi AA. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol 2009; 65: 12139.
  • 45
    Duttaroy A, Yoburn BC. The effect of intrinsic efficacy on opioid tolerance. Anesthesiology 1995; 82: 122636.
  • 46
    Gourlay G. Different opioids – same actions? In: Opioid Sensitivity of Chronic Noncancer Pain, eds Kalso E, McQuay HJ, Wiesenfeld-Hallin Z, Progess in Pain Research and Management. Seattle: JASP Press, 1999; 14: 97116.
  • 47
    Kanaan M, Daali Y, Dayer P, Desmeules J. Uptake/efflux transport of tramadol enantiomers and O-desmethyl-tramadol: focus on P-glycoprotein. Basic Clin Pharmacol Toxicol 2009; 105: 199206.
  • 48
    Keith DE, Anton B, Murray SR, Zaki PA, Chu PC, Lissin DV, Monteillet-Agius G, Stewart PL, Evans CJ, von ZM. mu-opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Mol Pharmacol 1998; 53: 37784.
  • 49
    Kumar P, Sunkaraneni S, Sirohi S, Dighe SV, Walker EA, Yoburn BC. Hydromorphone efficacy and treatment protocol impact on tolerance and mu-opioid receptor regulation. Eur J Pharmacol 2008; 597: 3945.
  • 50
    Lemberg KK, Siiskonen AO, Kontinen VK, Yli-Kauhaluoma JT, Kalso EA. Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia. Anesth Analg 2008; 106: 46370.
  • 51
    Leppert W, Luczak J. The role of tramadol in cancer pain treatment – a review. Support Care Cancer 2005; 13: 517.
  • 52
    Lotsch J. Opioid metabolites. J Pain Symptom Manage 2005; 29: (5 Suppl.): S1024.
  • 53
    McRae A, Sonne S. Opioid equivalency: a review. J Pharm Pract 1998; 11: 394405.
  • 54
    Medzihradsky F, Emmerson PJ, Mousigian CA. Lipophilicity of opioids determined by a novel micromethod. J Pharmacol Toxicol Methods 1992; 27: 679.
  • 55
    Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007; 132: 289300.
  • 56
    Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated. Pain 1997; 73: 1517.
  • 57
    Tzschentke TM, Christoph T, Kogel B, Schiene K, Hennies HH, Englberger W, Haurand M, Jahnel U, Cremers TI, Friderichs E, De VJ. (–)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007; 323: 26576.
  • 58
    Vallejo R, Barkin RL, Wang VC. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Phys 2011; 14: E34360.
  • 59
    Xie R, Hammarlund-Udenaes M. Blood-brain barrier equilibration of codeine in rats studied with microdialysis. Pharm Res 1998; 15: 5705.
  • 60
    Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance. Anesth Analg 2005; 101: 72834.
  • 61
    Avdeef A, Barrett DA, Shaw PN, Knaggs RD, Davis SS. Octanol-, chloroform-, and propylene glycol dipelargonat-water partitioning of morphine-6-glucuronide and other related opiates. J Med Chem 1996; 39: 437781.
  • 62
    Leander JD. Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology 1987; 26: 14457.
  • 63
    Andresen T, Staahl C, Oksche A, Mansikka H, Arendt-Nielsen L, Drewes AM. Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain. Br J Pharmacol 2011; 164: 93445.
  • 64
    Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol 1998; 56: 5539.
  • 65
    Volpe DA, Mahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, Kropp TJ, Verbois SL. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 2011; 59: 38590.
  • 66
    Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995; 274: 126370.
  • 67
    Tzschentke TM, Jahnel U, Kogel B, Christoph T, Englberger W, De VJ, Schiene K, Okamoto A, Upmalis D, Weber H, Lange C, Stegmann JU, Kleinert R. Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule. Drugs Today (Barc) 2009; 45: 48396.
  • 68
    Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage 2005; 29: (5 Suppl.): S29.
  • 69
    Bodnar RJ. Endogenous opiates and behavior: 2009. Peptides 2010; 31: 232559.
  • 70
    Chizh BA, Priestley T, Rowbotham M, Schaffler K. Predicting therapeutic efficacy – experimental pain in human subjects. Brain Res Rev 2009; 60: 24354.
  • 71
    Dolgin E. Animalgesic effects. Nat Med 2010; 16: 123740.
  • 72
    Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review. Br J Clin Pharmacol 2009; 68: 14968.
  • 73
    Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004; 112: 37280.
  • 74
    Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007; 8: 4153.
  • 75
    Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology (Bethesda) 2008; 23: 37180.
  • 76
    Drewes AM, Gregersen H, rendt-Nielsen L. Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003; 38: 111530.
  • 77
    Curatolo M, Petersen-Felix S, Gerber A, rendt-Nielsen L. Remifentanil inhibits muscular more than cutaneous pain in humans. Br J Anaesth 2000; 85: 52932.
  • 78
    Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L, Drewes AM. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006; 123: 2836.
  • 79
    Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, Dahan A. Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet 2005; 42: 5837.
  • 80
    Eisenach JC, Carpenter R, Curry R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain 2003; 101: 8995.
  • 81
    Arendt-Nielsen L, Olesen AE, Staahl C, Menzaghi F, Kell S, Wong GY, Drewes AM. Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain. Anesthesiology 2009; 111: 61624.
  • 82
    Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K, Hansen SH, Arendt-Nielsen L, Drewes AM. Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 2008; 48: 61931.
  • 83
    Sengupta JN, Snider A, Su X, Gebhart GF. Effects of kappa opioids in the inflamed rat colon. Pain 1999; 79: 17585.
  • 84
    Staahl C, Dimcevski G, Andersen SD, Thorsgaard N, Christrup LL, Arendt-Nielsen L, Drewes AM. Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study. Scand J Gastroenterol 2007; 42: 38390.
  • 85
    Bruera E, Belzile M, Pituskin E, Fainsinger R, Darke A, Harsanyi Z, Babul N, Ford I. Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J Clin Oncol 1998; 16: 32229.
  • 86
    Koppert W, Ihmsen H, Korber N, Wehrfritz A, Sittl R, Schmelz M, Schuttler J. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005; 118: 1522.
  • 87
    Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM. Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 2010; 70: 189200.
  • 88
    Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler J, Schmelz M. A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology 2001; 95: 395402.
  • 89
    Brainin-Mattos J, Smith ND, Malkmus S, Rew Y, Goodman M, Taulane J, Yaksh TL. Cancer-related bone pain is attenuated by a systemically available delta-opioid receptor agonist. Pain 2006; 122: 17481.
  • 90
    Delaney A, Fleetwood-Walker SM, Colvin LA, Fallon M. Translational medicine: cancer pain mechanisms and management. Br J Anaesth 2008; 101: 8794.
  • 91
    Andresen T, Upton RN, Foster DJ, Christrup LL, Arendt-Nielsen L, Drewes AM. Pharmacokinetic/pharmacodynamic relationships of transdermal buprenorphine and fentanyl in experimental human pain models. Basic Clin Pharmacol Toxicol 2011; 108: 27484.
  • 92
    Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 2010; 11: 85.
  • 93
    Rothwell PM. Can overall results of clinical trials be applied to all patients? Lancet 1995; 345: 16169.
  • 94
    Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev 2007; (4): CD003868.
  • 95
    Tassinari D, Sartori S, Tamburini E, Scarpi E, Raffaeli W, Tombesi P, Maltoni M. Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med 2008; 11: 492501.
  • 96
    Bekkering GE, Soares-Weiser K, Reid K, Kessels AG, Dahan A, Treede RD, Kleijnen J. Can morphine still be considered to be the standard for treating chronic pain? A systematic review including pair-wise and network meta-analyses. Curr Med Res Opin 2011; 27: 147791.
  • 97
    Dahan A, Olofsen E, Sigtermans M, Noppers I, Niesters M, Aarts L, Bauer M, Sarton E. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur J Pain 2011; 15: 25867.
  • 98
    Cullberg M, Eriksson UG, Wahlander K, Eriksson H, Schulman S, Karlsson MO. Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis. Clin Pharmacol Ther 2005; 77: 27990.
  • 99
    Yassen A, Olofsen E, Kan J, Dahan A, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats. Pharm Res 2008; 25: 18393.
  • 100
    Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology 2004; 101: 12019.
  • 101
    Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, Mercadante S, Meynadier J, Poulain P, Ripamonti C, Radbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda V. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001; 84: 58793.
  • 102
    Klepstad P, Kaasa S, Cherny N, Hanks G, De Conno F. Pain and pain treatments in European palliative care units. A cross sectional survey from the European Association for Palliative Care Research Network. Palliat Med 2005; 19: 47784.
  • 103
    Pergolizzi J, Alegre C, Blake D, Alen JC, Caporali R, Casser HR, Correa-Illanes G, Fernandes P, Galilea E, Jany R, Jones A, Mejjad O, Morovic-Vergles J, Oteo AA, Radrigan Araya FJ, Simoes ME, Uomo G. Current considerations for the treatment of severe chronic pain: the potential for tapentadol. Pain Pract 2011; 2: 12:290306.
  • 104
    Stone P, Minton O. European Palliative Care Research collaborative pain guidelines. Central side-effects management: what is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliat Med 2011; 25: 43141.
  • 105
    Laugsand EA, Kaasa S, Klepstad P. Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations. Palliat Med 2011; 25: 44253.
  • 106
    Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage 1997; 13: 25461.
  • 107
    Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain 2002; 3: 37784.
  • 108
    Eisenstein TK, Rahim RT, Feng P, Thingalaya NK, Meissler JJ. Effects of opioid tolerance and withdrawal on the immune system. J Neuroimmune Pharmacol 2006; 1: 23749.
  • 109
    Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev 2006; 32: 30415.
  • 110
    Mercadante S, Ferrera P, Villari P, Casuccio A, Intravaia G, Mangione S. Frequency, indications, outcomes, and predictive factors of opioid switching in an acute palliative care unit. J Pain Symptom Manage 2009; 37: 63241.
  • 111
    Mercadante S, Ferrera P, Villari P, Adile C, Casuccio A. Switching from oxycodone to methadone in advanced cancer patients. Support Care Cancer 2012; 20: 1914.
  • 112
    Kanbayashi Y, Hosokawa T, Okamoto K, Fujimoto S, Konishi H, Otsuji E, Yoshikawa T, Takagi T, Miki T, Taniwaki M. Factors predicting requirement of high-dose transdermal fentanyl in opioid switching from oral morphine or oxycodone in patients with cancer pain. Clin J Pain 2011; 27: 6647.
  • 113
    Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL III. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009; 10: 44785.
  • 114
    Macintyre PE, Jarvis DA. Age is the best predictor of postoperative morphine requirements. Pain 1996; 64: 35764.
  • 115
    Niesters M, Dahan A, Kest B, Zacny J, Stijnen T, Aarts L, Sarton E. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain 2010; 151: 618.
  • 116
    Knudsen AK, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A, Klepstad P. Which variables are associated with pain intensity and treatment response in advanced cancer patients? – Implications for a future classification system for cancer pain. Eur J Pain 2011; 15: 3207.
  • 117
    McQuay HJ, Carroll D, Faura CC, Gavaghan DJ, Hand CW, Moore RA. Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther 1990; 48: 23644.
  • 118
    Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004; (3): CD004847.
  • 119
    Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001; 19: 2898904.
  • 120
    Riley J, Ross JR, Rutter D, Wells AU, Goller K, du Bois R, Welsh K. No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Support Care Cancer 2006; 14: 5664.
  • 121
    Slatkin NE. Opioid switching and rotation in primary care: implementation and clinical utility. Curr Med Res Opin 2009; 25: 213350.
  • 122
    Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci 2001; 22: 6770.
  • 123
    Nielsen CK, Ross FB, Smith MT. Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat. J Pharmacol Exp Ther 2000; 295: 919.
  • 124
    Pasternak GW. Molecular insights into mu opioid pharmacology: from the clinic to the bench. Clin J Pain 2010; 26 (Suppl. 10): S39.
  • 125
    Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and the limitations of the equianalgesic dose table. J Pain Symptom Manage 2009; 38: 42639.
  • 126
    Fine PG, Portenoy RK. Establishing ‘best practices’ for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage 2009; 38: 41825.
  • 127
    Mercadante S, Caraceni A. Conversion ratios for opioid switching in the treatment of cancer pain: a systematic review. Palliat Med 2011; 25: 50415.
  • 128
    Portenoy RK. Treatment of cancer pain. Lancet 2011; 377: 223647.
  • 129
    NIH 1998. National Institute of Health.New Directions in Pain Research. 1998. Available at (last accessed 29 May 2012).
  • 130
    Gustavsson A, Bjorkman J, Ljungcrantz C, Rhodin A, Rivano-Fischer M, Sjolund KF, Mannheimer C. Socio-economic burden of patients with a diagnosis related to chronic pain – Register data of 840,000 Swedish patients. Eur J Pain 2011; 16: 28999.
  • 131
    Ritzwoller DP, Crounse L, Shetterly S, Rublee D. The association of comorbidities, utilization and costs for patients identified with low back pain. BMC Musculoskelet Disord 2006; 7: 72.
  • 132
    Berger A, Dukes EM, Oster G. Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 2004; 5: 1439.
  • 133
    Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain Phys 2008; 2: (Suppl.): S10520.
  • 134
    Leider HL, Dhaliwal J, Davis EJ, Kulakodlu M, Buikema AR. Healthcare costs and nonadherence among chronic opioid users. Am J Manag Care 2011; 17: 3240.
  • 135
    Kwong WJ, Diels J, Kavanagh S. Costs of gastrointestinal events after outpatient opioid treatment for non-cancer pain. Ann Pharmacother 2010; 44: 63040.
  • 136
    Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010; (1): CD006605.
  • 137
    Broekmans S, Dobbels F, Milisen K, Morlion B, Vanderschueren S. Determinants of medication underuse and medication overuse in patients with chronic non-malignant pain: a multicenter study. Int J Nurs Stud 2010; 47: 140817.
  • 138
    Neighbors DM, Bell TJ, Wilson J, Dodd SL. Economic evaluation of the fentanyl transdermal system for the treatment of chronic moderate to severe pain. J Pain Symptom Manage 2001; 21: 12943.
  • 139
    Radbruch L, Sabatowski R, Petzke F, Brunsch-Radbruch A, Grond S, Lehmann KA. Transdermal fentanyl for the management of cancer pain: a survey of 1005 patients. Palliat Med 2001; 15: 30921.
  • 140
    Vondrackova D, Leyendecker P, Meissner W, Hopp M, Szombati I, Hermanns K, Ruckes C, Weber S, Grothe B, Fleischer W, Reimer K. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008; 9: 114454.
  • 141
    Buynak R, Shapiro DY, Okamoto A, Van Hove I, Rauschkolb C, Steup A, Lange B, Lange C, Etropolski M. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010; 11: 1787804.
  • 142
    Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008; 358: 233243.
  • 143
    Annemans L. Pharmacoeconomic impact of adverse events of long-term opioid treatment for the management of persistent pain. Clin Drug Investig 2011; 31: 7386.