- Email: [email protected]
287 CRITICAL ISSUES ON OPIOIDS IN CHRONIC NON-CANCER PAIN: A COHORT STUDY
Poster Sessions / European Journal of Pain 13 (2009) S55–S285
In the masseter model, hypertonic saline (HS) injected into the muscle evokes a paw shaking behaviour that is considered as an index of nociception. In the gastrocnemius model, after HS injection, the time that rat spent with lifted or retracted paw was recorded. Modification of these behavioural parameters and of the threshold of tail withdrawal in the tail flick test, after treatment with opioid agonists and antagonists, was studied. Both morphine and loperamide reduced HS-induced nociceptive behaviours on masseter model. These effects were antagonized by naloxone and naloxone-methiodide. However, on gastrocnemius model or tail flick test, morphine, but not loperamide, was able to avoid the nociceptive behaviours; this effect was only antagonized by naloxone. Our results suggest that peripheral opioid receptors are implicated in masseter pain induced by HS injection, whereas on gastrocnemius pain, as well as in tail flick test, mainly central opioid receptors are involved. Supported by SAF2006–13391-CO3–01 285 DIFFERENTIAL EFFECTS OF MORPHINE AND OXYCODONE IN EXPERIMENTALLY EVOKED CUTANEOUS AND VISCERAL HYPERALGESIA – A HUMAN TRANSLATIONAL STUDY A.E. Olesen1,2 *, C. Staahl1,2 , L. Arendt-Nielsen2 , A.M. Drewes1,2 . 1 Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark; 2 Center for Sensory-Motor Interactions (SMI), Department of Health Science and Technology, Aalborg University., Aalborg, Denmark Chronic pain associated with hyperalgesia can be difficult to treat with traditional m-opioid agonists. Previous studies have shown more beneficial effects of oxycodone compared to morphine in clinical hyperalgesia. The aim was to investigate differentiated effects of morphine and oxycodone after experimentally evoked hyperalgesia. Twenty-four healthy volunteers were randomized to equipotent treatment with morphine (30–mg, p.o.) and oxycodone (15 mg, p.o.) or placebo in a crossover study. Visceral sensitization was induced by esophageal acid and capsaicin perfusion. Skin sensitization was induced by capsaicin cream on one forearm and areas of secondary hyperalgesia to brush and von Frey hair stimulation were measured. Experimental pain models including heat stimulation in normal skin, muscle pressure and esophageal mechanical, heat and electrical stimulations were applied. Areas of hyperalgesia assessed with Von Frey hair were not reduced by any of the opioids after skin sensitization (P = 0.6), whereas the areas of allodynia assessed with brush was increased by morphine (P = 0.02). Oxycodone was superior to morphine in normal skin heat stimulation (P = 0.04) and in muscle pressure stimulation (P < 0.001). In the esophageal experiments oxycodone showed better analgesic effect compared to morphine to the heat (P = 0.003) and electrical (P = 0.04) stimulation. Differentiated effects of morphine and oxycodone were found in response to skin, muscle and esophageal pain stimulation. As these data supports previous investigations in chronic pain patients, the present study seems to act as a translational model between experimental and clinical conditions. 286 PAIN CONTROL BY PREVENTION OF OPIOID PEPTIDE DEGRADATION IN PERIPHERAL INFLAMED TISSUE A. Schreiter1 *, C. Gore1 , B.P. Roques2 , C. Stein1 , H. Machelska1 . 1 Charite-Campus Benjamin Franklin Anaesthesiologie, Berlin, Germany; 2 Pharmaleads, Paris, France Background and Aims: Degradation of opioid peptides by aminopeptidase N (APN) and neutral endopeptidase (NEP) has been extensively examined in the central nervous system. Our goal was to investigate the prevention of opioid peptide catabolism with
S89
inhibitors of NEP (thiorphan) and of APN (bestatin) as well as a novel dual inhibitor RB3008 to enhance antinociceptive effects of opioids in inflamed painful tissue. Methods: Experiments were performed at 4 days after injection of complete Freund’s adjuvant into one hind paw in rats. Antinociceptive effects of peptidase inhibitors were assessed with the paw pressure test. Enzymatic activity of APN and NEP was analyzed using immune cells or sciatic nerves isolated from inflamed paws, and was measured spectrometricaly or with radioimmunoassay. Results: Co-injection of thiorphan and bestatin or application of RB3008 into inflamed paws produced dose-dependent antinociception. In in vitro leukocyte or sciatic nerve preparations APN and NEP cleaved their specific exogenously added substrates (Ala-b-naphthylamin and Suc-Ala-Ala-Phe-p-nitroanilin, respectively) that could be blocked with single and dual inhibitors. Importantly, degradation of Met- and Leu-enkephalin, but not of b-endorphin, was prevented by combination of thiorphan and bestatin or by RB3008. Conclusions: We show for the first time that degradation of opioid peptides can be prevented by blockade of APN and NEP expressed in immune cells and peripheral nerves in painful inflammation. Enkephalins appear as preferred substrates for NEP and APN. Inhibiting the enzymatic degradation of opioids offers a promising strategy for the pain control without adverse centrally-mediated side effects. 287 CRITICAL ISSUES ON OPIOIDS IN CHRONIC NON-CANCER PAIN: A COHORT STUDY P. Sjøgren1 *, M. Grønbæk2 , V. Peuckmann3 , O. Ekholm4 . 1 Unit of Palliative Medicine, Rigshospitalet, Copenhagen 2100Ø, Denmark; 2 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; 3 Department of Anaesthesiology and Department of Palliative Medicine, RWTH Aachen University Hospital, Aachen, Germany; 4 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark The Health Interview Surveys of adult Danish citizens have been carried out in 1987, 1994, 2000 and 2005. The aim of the study was to investigate the incidence for developing and recovering from chronic pain and to investigate the consequences of opioid use from 2000 to 2005. In 2000, a sample of 16.684 individuals was included. Respondents with cancer diagnosis were excluded from all analyses. 10,065 individuals (62.5%) completed an interview and a questionnaire. A sub-sample consisting of 5,316 subjects, who participated in the surveys in 1994 and 2000 were drawn. 486 persons, aged 16–21 years, and 110 persons who had obtained citizenship in the period were added to make the sample representative. 3,649 individuals (61.7%) completed the interview and the questionnaire. In 2005, 2,242 of these subjects were available for re-examination. The respondents having chronic/longlasting pain >6 months reported regular use of medications, heathrelated quality of life, educational status and physical strain of occupation. Our findings indicated that individuals with chronic pain using strong opioids have a higher risk of death than individuals without chronic pain (HR: 1.51; 95% CI: 0.84–2.69) and the odds for recovery from chronic pain were 4-fold decreased in opioid users. The annual incidence for development of and recovery from chronic pain was 2.7% and 9.4%, respectively. In conclusion, opioid use reduced recovery from chronic pain and seemed to increase mortality.
In the masseter model, hypertonic saline (HS) injected into the muscle evokes a paw shaking behaviour that is considered as an index of nociception. In the gastrocnemius model, after HS injection, the time that rat spent with lifted or retracted paw was recorded. Modification of these behavioural parameters and of the threshold of tail withdrawal in the tail flick test, after treatment with opioid agonists and antagonists, was studied. Both morphine and loperamide reduced HS-induced nociceptive behaviours on masseter model. These effects were antagonized by naloxone and naloxone-methiodide. However, on gastrocnemius model or tail flick test, morphine, but not loperamide, was able to avoid the nociceptive behaviours; this effect was only antagonized by naloxone. Our results suggest that peripheral opioid receptors are implicated in masseter pain induced by HS injection, whereas on gastrocnemius pain, as well as in tail flick test, mainly central opioid receptors are involved. Supported by SAF2006–13391-CO3–01 285 DIFFERENTIAL EFFECTS OF MORPHINE AND OXYCODONE IN EXPERIMENTALLY EVOKED CUTANEOUS AND VISCERAL HYPERALGESIA – A HUMAN TRANSLATIONAL STUDY A.E. Olesen1,2 *, C. Staahl1,2 , L. Arendt-Nielsen2 , A.M. Drewes1,2 . 1 Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark; 2 Center for Sensory-Motor Interactions (SMI), Department of Health Science and Technology, Aalborg University., Aalborg, Denmark Chronic pain associated with hyperalgesia can be difficult to treat with traditional m-opioid agonists. Previous studies have shown more beneficial effects of oxycodone compared to morphine in clinical hyperalgesia. The aim was to investigate differentiated effects of morphine and oxycodone after experimentally evoked hyperalgesia. Twenty-four healthy volunteers were randomized to equipotent treatment with morphine (30–mg, p.o.) and oxycodone (15 mg, p.o.) or placebo in a crossover study. Visceral sensitization was induced by esophageal acid and capsaicin perfusion. Skin sensitization was induced by capsaicin cream on one forearm and areas of secondary hyperalgesia to brush and von Frey hair stimulation were measured. Experimental pain models including heat stimulation in normal skin, muscle pressure and esophageal mechanical, heat and electrical stimulations were applied. Areas of hyperalgesia assessed with Von Frey hair were not reduced by any of the opioids after skin sensitization (P = 0.6), whereas the areas of allodynia assessed with brush was increased by morphine (P = 0.02). Oxycodone was superior to morphine in normal skin heat stimulation (P = 0.04) and in muscle pressure stimulation (P < 0.001). In the esophageal experiments oxycodone showed better analgesic effect compared to morphine to the heat (P = 0.003) and electrical (P = 0.04) stimulation. Differentiated effects of morphine and oxycodone were found in response to skin, muscle and esophageal pain stimulation. As these data supports previous investigations in chronic pain patients, the present study seems to act as a translational model between experimental and clinical conditions. 286 PAIN CONTROL BY PREVENTION OF OPIOID PEPTIDE DEGRADATION IN PERIPHERAL INFLAMED TISSUE A. Schreiter1 *, C. Gore1 , B.P. Roques2 , C. Stein1 , H. Machelska1 . 1 Charite-Campus Benjamin Franklin Anaesthesiologie, Berlin, Germany; 2 Pharmaleads, Paris, France Background and Aims: Degradation of opioid peptides by aminopeptidase N (APN) and neutral endopeptidase (NEP) has been extensively examined in the central nervous system. Our goal was to investigate the prevention of opioid peptide catabolism with
S89
inhibitors of NEP (thiorphan) and of APN (bestatin) as well as a novel dual inhibitor RB3008 to enhance antinociceptive effects of opioids in inflamed painful tissue. Methods: Experiments were performed at 4 days after injection of complete Freund’s adjuvant into one hind paw in rats. Antinociceptive effects of peptidase inhibitors were assessed with the paw pressure test. Enzymatic activity of APN and NEP was analyzed using immune cells or sciatic nerves isolated from inflamed paws, and was measured spectrometricaly or with radioimmunoassay. Results: Co-injection of thiorphan and bestatin or application of RB3008 into inflamed paws produced dose-dependent antinociception. In in vitro leukocyte or sciatic nerve preparations APN and NEP cleaved their specific exogenously added substrates (Ala-b-naphthylamin and Suc-Ala-Ala-Phe-p-nitroanilin, respectively) that could be blocked with single and dual inhibitors. Importantly, degradation of Met- and Leu-enkephalin, but not of b-endorphin, was prevented by combination of thiorphan and bestatin or by RB3008. Conclusions: We show for the first time that degradation of opioid peptides can be prevented by blockade of APN and NEP expressed in immune cells and peripheral nerves in painful inflammation. Enkephalins appear as preferred substrates for NEP and APN. Inhibiting the enzymatic degradation of opioids offers a promising strategy for the pain control without adverse centrally-mediated side effects. 287 CRITICAL ISSUES ON OPIOIDS IN CHRONIC NON-CANCER PAIN: A COHORT STUDY P. Sjøgren1 *, M. Grønbæk2 , V. Peuckmann3 , O. Ekholm4 . 1 Unit of Palliative Medicine, Rigshospitalet, Copenhagen 2100Ø, Denmark; 2 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; 3 Department of Anaesthesiology and Department of Palliative Medicine, RWTH Aachen University Hospital, Aachen, Germany; 4 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark The Health Interview Surveys of adult Danish citizens have been carried out in 1987, 1994, 2000 and 2005. The aim of the study was to investigate the incidence for developing and recovering from chronic pain and to investigate the consequences of opioid use from 2000 to 2005. In 2000, a sample of 16.684 individuals was included. Respondents with cancer diagnosis were excluded from all analyses. 10,065 individuals (62.5%) completed an interview and a questionnaire. A sub-sample consisting of 5,316 subjects, who participated in the surveys in 1994 and 2000 were drawn. 486 persons, aged 16–21 years, and 110 persons who had obtained citizenship in the period were added to make the sample representative. 3,649 individuals (61.7%) completed the interview and the questionnaire. In 2005, 2,242 of these subjects were available for re-examination. The respondents having chronic/longlasting pain >6 months reported regular use of medications, heathrelated quality of life, educational status and physical strain of occupation. Our findings indicated that individuals with chronic pain using strong opioids have a higher risk of death than individuals without chronic pain (HR: 1.51; 95% CI: 0.84–2.69) and the odds for recovery from chronic pain were 4-fold decreased in opioid users. The annual incidence for development of and recovery from chronic pain was 2.7% and 9.4%, respectively. In conclusion, opioid use reduced recovery from chronic pain and seemed to increase mortality.