Pharmacy World and Science

, Volume 18, Issue 1, pp 1–15 | Cite as

Pharmacotherapy of opioids: present and future developments

  • T. F. Meert


The clinically available opiolds have different physicochemical properties, resulting in differences in clinical profile with regard to potency, onset, and duration of activity. However, they all have comparable side-effects after acute systemic application. Several approaches can be used to overcome these side-effects. The following approaches, with special emphasis on the perioperative use of the opioids, are discussed: (1) the use of alternative routes of administration, such as via the spine (epidurally and intrathecally); (2) optimization of opioid delivery by means of slow-release preparations, chronic infusions with indwelling catheters, and transdermal delivery systems; (3) use of additional agents to potentiate the analgesic properties of the oploids so that the dose of oploid can be reduced; and (4) searching for new analgesics on the basis of knowledge of the pain-transmission system and the different opioid receptors with their functional interactions.


Administration, transdermal Adverse effects Analgesia, epidural Analgesics, opioid Drug development Pharmacology Receptors, opioid 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Meert TF. Pharmacological effects of epidural opioids. Ther Today 1989;8:1–9.Google Scholar
  2. 2.
    White PF. Clinical uses of intravenous anesthetic and analgesic infusions. Anesth Analg 1989;68:161–71.Google Scholar
  3. 3.
    De Lange S, Boscoe MJ, Stanley TH, Pace N. Comparison of sufentanil-O2 and fentanyl-O2 for coronary artery surgery. Anesthesiology 1982;56:112–8.Google Scholar
  4. 4.
    Flacke JW, Bloor BC, Kripke BJ. Comparison of morphine, meperidine; fentanyl and sufentanil in balanced anesthesia: a double-blind study. Anesth Analg 1985;64:897–910.Google Scholar
  5. 5.
    Bovill JG. Which potent opioid? Important criteria for selection. Drugs 1987;33:520–30.Google Scholar
  6. 6.
    Philbin DM, Rosow CE, Schneider RC, Koski G, D'Ambra MN. Fentanyl and sufentanil anesthesia revisited: how much is enough? Anesthesiology 1990;73:5–11.Google Scholar
  7. 7.
    Clotz MA, Nahata MC. Drug review: clinical uses of fentanyl, sufentanil and alfentanil. Clin Pharm 1991;10:581–93.Google Scholar
  8. 8.
    Ziser A, Murray MJ. Postoperative pain. Analgesics make a difference in many ways. Postgrad Med 1993;93:173–89.Google Scholar
  9. 9.
    Willens JS, Myslinski NR. Pharmacodynamics, pharmacokinetics, and clinical uses of fentanyl, sufentanil and alfentanil. Heart Lung 1993;22:239–51.Google Scholar
  10. 10.
    Bagley JR, Kudzma LV, Lalinde NL, Colapret JA, Huang BS, Lin BS. Evolution of the 4-anilidopiperidine class of opioid analgesics. Med Res Rev 1991;11(4):403–36.Google Scholar
  11. 11.
    Feldman PL, James MK, Brackeen MF Bilotta JM, Schuster SV, Lahey AP, et al. Design, synthesis and pharmacological evaluation of ultrashort-to long-acting opioid analgesics. J. Med Chem 1991;34:2202–8.Google Scholar
  12. 12.
    France CP, Winger G, Medzihradsky F, Seggel MR, Rice KC, Woods JH. Mirfentanil: pharmacological profile of a novel fentanyl derivative with opioid and nonopioid effects. J Pharmacol Exp Ther 1991;258:502–10.Google Scholar
  13. 13.
    James MK. Remifentanil and anaesthesia for the future. Expert Opin Invest Drugs 1994;3:331–40.Google Scholar
  14. 14.
    France CP, Gerak LR, Flynn D, Winger GD, Medzihradsky F, Bagley JR, et al. Behavioral, effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys. J Pharmacol Exp Ther 1995;274:17–28.Google Scholar
  15. 15.
    Rosow CE. Newer opioid agonists. Ballieres Clin Anaesthesiol 1995;9:67–82.Google Scholar
  16. 16.
    Lemmens HJ, Egan TD, Fiset P, Stanski DR. Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil. Anesth Analg 1995;80:1206–11.Google Scholar
  17. 17.
    Glass PS, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (C187084B). Anesth Analg 1993;77:1031–40.Google Scholar
  18. 18.
    Hoffman WE, Cunningham F, James MK, Baughman VL, Albrecht RF. Effects of remifentanil, a new short-acting opioid, on cerebral blood flow, brain electrical activity, and intracranial pressure in dogs anaesthetized with isoflurane and nitrous oxide. Anaesthesiology 1993;79:107–13.Google Scholar
  19. 19.
    Egan TD. Remifentanil pharmacokinetics and pharmacodynamics; a preliminary appraisal. Clin Pharmacokinet 1995;29:80–94.Google Scholar
  20. 20.
    Lemmens HJM. Opioids in intravenous anaesthesia. Anaesth Pharmacol Rev 1995;3:67–73.Google Scholar
  21. 21.
    Regoli D, Boudon A, Fauchére J-L. Receptors and antagonists for Substance P and related peptides. Pharmacol Rev 1994;46:551–99.Google Scholar
  22. 22.
    Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–6.Google Scholar
  23. 23.
    Behar M, Olswang D, Magora F, Davidson JT. Epidural morphine in the treatment of pain. Lancet 1979;1:527–9.Google Scholar
  24. 24.
    Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anaesthesia 1979;50:149–51.Google Scholar
  25. 25.
    Niemegeers CJE, Schellekens KHL, van Bever WFM, Janssen PAJ. Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs. Arzneimittelforschung [Drung Res] 1976;26:1551–6.Google Scholar
  26. 26.
    Donadoni R, Rolly G, Noorduin H, Vanden Bussche G. Epidural sulentanil for post-operative pain relief. Anaesthesia 1985;40:634–8.Google Scholar
  27. 27.
    Verborgh C, van der Auwera D, van Droogenbroek E, Camu F. Epidural sufentanil for postsurgical pain relief. Eur J Anaesthesiol 1986;3:313–20.Google Scholar
  28. 28.
    Whtting WC, Sandler AN, Lau LC, Chovaz PM, Slavchenko P, Daley D, et al. Analgesic and respiratory effects of epidural sufentanil in patients following thoracotomy. Anesthesiology 1988;69:36–43.Google Scholar
  29. 29.
    Koren G, Sandler AN, Klein J, Whiting WC, Lau LC, Slavchenko P, et al. Relationship between the pharmacokinetics and the analgesic and respiratory pharmacodynamics of epidural sufentanil. Clin Pharmacol Ther 1989;45:458–62.Google Scholar
  30. 30.
    Rosen M, Dailey P, Hughes S, Leicht C, Shnider S, Jackson C, et al. Epidural sufentanil for postoperative analgesia after cesarian section. Anesthesiology 1988;68:448–54.Google Scholar
  31. 31.
    Madej TH, Strunin L. Comparison of epidural fentanyl with sufentanil. Analgesia and side effects after a single bolus dose during elective caesarean section. Anaesthesia 1987;42:1156–61.Google Scholar
  32. 32.
    Cohen SE, Tan S, White PF. Sufentanil analgesia following cesarean section: epidural versus intravenous administration. Anesthesiology 1988;68;129–34.Google Scholar
  33. 33.
    Ionescu TI, Taverne RHT, Houweling P, Schouten ANJ, Schinmel G, van der Tweel I, et al. A study of epidural morphine and sufentanil anesthesia for abdominal aortic surgery. Acta Anaesthesiol Belg 1989;40:65–77.Google Scholar
  34. 34.
    Rosseel PMJ, van der Broek WGM, Boer EC, Prakash O. Epidural sufentanil for intra-and postoperative analgesia in thoracic surgery: a comparative study with intravenous sufentanil. Acta Anaesth Scand 1988;32:193–8.Google Scholar
  35. 35.
    Hasenbos MAWM, Gielen MJM, Bos JAG, Tielbeek EA, Stanton-Hicks M. High thoracic epidural sufentanil for posttnoracotomy pain: influence of epinephrine as an adjuvanta double-blind study Anesthesiology 1988;69:1017–22.Google Scholar
  36. 36.
    Stanton-Hicks MD, Gielen M, Hasenbos M, Matthijssen C, van Heteren JA, Crul J. High thoracic epidural with sufentanil for post-thoracotomy pain. Reg Anesth 1988;13:62–8.Google Scholar
  37. 37.
    Dyer RA, Anderson BJ, Michell WL, Hall JM. Postoperative pain control with a continuous infusion of epidural sufentanil in the intensive care unit: a comparison with epidural morphine. Anesth Analg 1990;71:130–6.Google Scholar
  38. 38.
    Hasenbos M, Eckhaus M, Slappendel R, Gielen M. Continuous high thoracic epidural administration of bupivacaine with sufentanil or nicomorphine for postoperative pain relief after thoracic surgery. Reg Anesth 1989;14:212–8.Google Scholar
  39. 39.
    Lubenow TR, Fischer RL, Besser TP, McCarthy RJ, Newman LM, Ivankovich AD. Comparison of continuous epidural infusions of sufentanil-bupivacaine with morphine-bupivacaine. Anesthesiology 1988; 69 (3A): A397.Google Scholar
  40. 40.
    Vercauteren MP. PCA by epidural route (PCEA). Acta Anaesth Belg 1992;43:33–9.Google Scholar
  41. 41.
    Boersma FP, Noorduin H, Vanden Bussche G. Epidural sufentanil for cancer pain control in outpatients. Reg Anesth 1989;14:293–7.Google Scholar
  42. 42.
    Boersma FP, Meert TF, Ten Kate A, Pieters W, Noorduin H. Cancer pain control by epidural sufentanil. Eur J Pain 1990;11:76–80.Google Scholar
  43. 43.
    Devaux C, Zickler P, Mangez JF, Tessier C, Alibert F. Pharmacologie clinique des opiaces par voie medullaire. Swiss Med 1983;5:13–21.Google Scholar
  44. 44.
    Hassenbusch SJ, Stanton-Hicks MD, Soukup J, Covington EC, Boland MB, Sufentanil citrate and morphine/bupivacaine as alternative agents in chronic epidural infusions for intractable non-cancer pain. Neurosurgery 1991;29:76–82.Google Scholar
  45. 45.
    Van den Hoogen RHWM, Colpaert FC. Epidural and subcutaneous morphine, meperidine (pethidine), fentanyl and sufentanil in the rat: analgesia and other in vivo pharmacologic effects. Anesthesiology 1987;66:186–94.Google Scholar
  46. 46.
    Van den Hoogen RHWM, Bervoets KJW, Colpaert FC. Respiratory effects of epidural and subcutaneous morphine, meperidine, fentanyl and sufentanil in the rat. Anesth Analg 1988;67:1071–8.Google Scholar
  47. 47.
    Colpaert FC, Leysen JE, Michiels M, van den Hoogen RHWM. Epidural and intravenous sufentanil in the rat: Analgesia, opiate receptor binding, and drug concentrations in plasma and brain. Anesthesiology 1986;65:41–9.Google Scholar
  48. 48.
    Boersma FP, Meert TF, Vercauteren M. Spinal sufentanil in rats: Part I Epidural versus intrathecal sufentanil and morphine. Acta Anaesthesiol Scand 1992;36:187–92.Google Scholar
  49. 49.
    Edwards WT, White MJ, Xiao CS. A comparison of epidural and systemic narcotics in modification of vocalization behavior in the quinea pig. Pain 1987; Suppl 4: S397.Google Scholar
  50. 50.
    Aoki M, Senami M, Kitahata LM, Collins JG. Spinal sufentanil effects on spinal pain-transmission neurons in cats. Anesthesiology 1986;64:225–9.Google Scholar
  51. 51.
    Sabbe M, Mjanger E, Sosnowski M, Yaksh TL. Study on tolerance development after daily epidural injection of sufentanil in dogs. Anesthesiology 1988; 69: 3A.Google Scholar
  52. 52.
    Sabbe M, Mjanger E, Hill H, Yaksh T. Epidural sufentanil in dogs: Analgesia versus plasma concentration. Anesth Analg 1989; 68: S243.Google Scholar
  53. 53.
    Mollmann M, van Aken H, van Hemelrijck J, Lemmens E. Sufentanil for postoperative analgesia. Eur J Pain 1990;11:72–5.Google Scholar
  54. 54.
    Geller E, Chrubasik J, Graf R, Chrubasik S, Schulte-Monting J. A randomized double-blind comparison of epidural sufentanil versus intravenous sufentanil or epidural fentanyl analgesia after major abdominal surgery. Anesth Analg 1993;76:1243–50.Google Scholar
  55. 55.
    Taverne R, Ionescu T, Nuyten S. Comparative absorption and distribution pharmacokinetics of intravenous and epidural sufentanil for major abdominal surgery. Clin Pharmacokinet 1992;23:231–7.Google Scholar
  56. 56.
    Chrubasik J, Geller E, Graf R, Zbinden A, Thomson D. Epidural sufentanil versus intravenous sufentanil and epidural fentanyl for PCA treatment of post-operative pain. Eur J Anaesthesiol 1991;8:486–7.Google Scholar
  57. 57.
    Camann W, Minzter B, Denney R, Datta S. Intrathecal sufentanil for labor analgesia. Anesthesiology 1993;78:870–4.Google Scholar
  58. 58.
    Donadoni R, vermeulen H, Noorduin H, Rolly G. Intrathecal sufentanil as a supplement to subarachnoid anaesthesia with lignocaine. Br J Anaesthesiol 1987;59:1523–7.Google Scholar
  59. 59.
    Hansdottir V, Hedner T, Woestenborghs R, Nordberg G. The CSF and plasma pharmacokinetics of sufentanil after intrathecal administration. Anesthesiology 1991;74:264–9.Google Scholar
  60. 60.
    Grass JA. Sufentanil: clinical use as postoperative analgesic. Epidural/intrathecal route. J Pain Symptom Manage 1992;7:271–86.Google Scholar
  61. 61.
    Honet J, Arkoosh V, Norris M, Huffnagle J, Silverman N, Leighton B. Comparison among intrathecal fentanyl, meperidine and sufentanil for labor analgesia. Anesth Analg 1992;75:734–9.Google Scholar
  62. 62.
    Houweling PL, lonescu TI, Hoynck van Papendrecht A, Schimmel GH, Verkooyen R, Smalhout B. A haemodynamic comparison of epidural versus intrathecal sufentanil to supplement general anaesthesia for abdominal aortic surgery. Eur J Anaesthesiol 1992;9:95–103.Google Scholar
  63. 63.
    Meert TF, Lu HR, van Craenendonck H, Janssen PAJ. Comparison between epidural fentanyl, sufentanil, carfentanil, lofentanil and alfentanil in the rat: analgesia and other in vivo effects. Eur J Anaesthesiol 1988;5:313–21.Google Scholar
  64. 64.
    Van der Auwera D, Verborgh C, Camu F. Ahalgesic and cardiorespiratory effects of epidural sufentanil and morphine in humans. Anesth Analg 1987;66:999–1003.Google Scholar
  65. 65.
    Sinatra RS, Sevarino FB, Chung JH, Graef G, Paige D, Takla V, et al. Comparison of epidurally administered sufentanil, morphine and sufentanil-morphine combination for postoperative analgesia. Anesth Analg 1991;72:522–7.Google Scholar
  66. 66.
    Dottrens M, Rifat K, Morel D. Comparison of extradural administration of sufentanil, morphine and sufentanil-morphine combination after caesarean section. Br J Anaesthesiol 1992;69:9–12.Google Scholar
  67. 67.
    Cohen S, Amar D, Pantuck C, Weismann A, Landa S, Singer N. Postcesarean delivery epidural patient controlled analgesia. Anesthesiology 1993;78:486–91.Google Scholar
  68. 68.
    Vercauteren M, Meert TF, D'Hooghe R, Boersma F, Melis W. Spinal sufentanil in rats: Part III Effect of diluent volume on epidural sufentanil. Acta Anaesthesiol Scand 1992;36:305–8.Google Scholar
  69. 69.
    Vercauteren M, Meert TF, Boersma F, Melis W, Adriaensen H. Spinal sufentanil in rats: Part II Effect of adding bupivacaine to epidural sufentanil. Acta Anaesthesiol Scand 1992;36:245–9.Google Scholar
  70. 70.
    Meert TF, Noorduin H, Van Craenendonck H, Vermote P, Boersma FP, Janssen PAJ. Effects of adrenaline, an α2-adrenoreceptor agonist, the volume of injection, and the global pain state of the animal on the activity of epidural sufentanil. Acta Anaesthesiol Belg 1989;40:247–61.Google Scholar
  71. 71.
    Boersma FP, Heykants J, ten Kate A, Meert TF, Pieters W, Woestenborghs R. Sufentanil concentrations in the human spinal cord after long term epidural infusion. Clin J Pain 1991;4:199–203.Google Scholar
  72. 72.
    Haak-van der Lely F, van Kleef M, Burm M, Bovill P. An intraoperative comparison of lumbar with thoracic epidural sufentanil for thoracotomy. Reg Anesth 1991; 17: 1S.Google Scholar
  73. 73.
    Verborgh C, van der Auwera D, Noorduin H, Camu F. Epidural sufentanil for postoperative pain relief: effects of adrenaline. Eur J Anaesthesiol 1988;5:183–91.Google Scholar
  74. 74.
    Duckett JE, McDonnell T, Zebrowski M, Witte M. A comparison of thoracic versus lumbar continuous epidural infusions of sufentanil for postoperative pain relief after upper abdominal surgery. Anesthesiology 1986; 65: 3A.Google Scholar
  75. 75.
    Duckett JE, McDonnell T, Zebrowski M, Witte M. Lumbar versus thoracic continuous epidural sufentanil for postoperative analgesia after upper abdominal surgery. Anesth Analg 1987;66:S1-S19.Google Scholar
  76. 76.
    Vercauteren M, Moens F, Hanegreefs G. Modification of analgesic quality and side effects of epidural sufentanil. In: Scherpereel P, Meynadier J, Blond S, editors. The Pain Clinic II. Utrecht: VNU Science Press, 1987; 299–301.Google Scholar
  77. 77.
    Dickerson SE, Robinson DE, Leicht CH. Prolongation of postoperative sufentanil analgesia with epinephrine. Anesthesiology 1988; 69(3A): A681.Google Scholar
  78. 78.
    Klepper D, Sherrill DL, Boetger CL, Bromage PR. Analgesic and respiratory effects of extradural sufentanil in volunteers and the influence of adrenaline as an adjuvant. Br J Anaesth 1987;59:1147–56.Google Scholar
  79. 79.
    Leicht CH, Kelleher AJ, Robinson DE, Dickerson SE. Prolongation of postoperative epidural sufentanil analgesia with epinephrine. Anesth Analg 1990;70:323–5.Google Scholar
  80. 80.
    McMorland GH, Douglas MJ, Kim JHK, Kamani AA, Swenerton JE, Berkowitz J, et al. Epidural sufentanil for post-Caesarean section analgesia: lack of benefit of epinephrine. Can J Anaesth 1990;37:432–7.Google Scholar
  81. 81.
    Cousins MJ, Mather LE, Intrathecal and epidural administration of opioids. Anesthesiology 1984;61:276–310.Google Scholar
  82. 82.
    Laveaux M, Liem T, Hasenbos M, Harbers J. Thoracic epidural bupivacaine plus sufentanil: high concentration/how volume versus low concentration/high volume. Reg Anesth 1993;18:39–43.Google Scholar
  83. 83.
    Harbers JBM, Hasenbos MAWM, Gort C, Folgering H, Dirksen R, Gielen MJM. Ventilatory function and continuous high thoracic epidural administration of bupivacaine with sufentanil intravenously or epidurally: a double-blind comparison. Reg Anesth 1991;16:65–71.Google Scholar
  84. 84.
    Reynvoet M, Dionys J, Vermaut G, van Aken H. Surgical analgesia for knee arthroscopy with epidural lignocaine and sufentanil—effect of varying sufentanil doses. Acta Anaesth Belg 1990;41:319–5.Google Scholar
  85. 85.
    Mourisse J, Hasenbos M, Gielen M, Moll J, Cromheecke G. Epidural bupivacaine, sufentanil or the combination for post-thoracotomy pain. Acta Anaesthesiol Scand 1992;36:70–4.Google Scholar
  86. 86.
    Vandermeersch E. Epidural patient controlled analgesia with bupivacaine and sufentanil. Acta Anaesth Belg 1992;43:71–4.Google Scholar
  87. 87.
    Jorrot J, Lirzin J, Dailland Ph, Jacquino Conseiller Ch. Association sufentanil-bupivacaine a 0.25% par voie peridurale l'analgesie obstetricale. Comparaison avec fentanyl et un placebo. Ann, Fr Anesth Reanim 1989;8:321–5.Google Scholar
  88. 88.
    Phillips GH. Combined epidural sufentanil and bupivacaine for labor analgesia. Reg Anaesth 1987a;12:165–8.Google Scholar
  89. 89.
    Phillips GH. Epidural sufentanil/bupivacaine combinations for analgesia during labor: effect of varying sufentanil doses. Anesthesiology 1987;67:835–8.Google Scholar
  90. 90.
    Phillips G. Continuous infusion epidural analgesia in labor: the effect of adding sufentanil to 0.125% bupivacaine. Anesth Analg 1988;7:462–5.Google Scholar
  91. 91.
    Van Steenberge A, Debroux H, Noorduin H. Extradural bupivacaine with sufentanil for vaginal delivery. Br J Anaesth 1987;59:1518–22.Google Scholar
  92. 92.
    Vertommen J, Vandermeulen E, van Aken H, Vaes L, Soetens M, van Steenberge A, et al. The effects of the addition of sufentanil to 0.125% bupivacaine on the quality of analgesia during labor and on the incidence of instrumental deliveries. Anesthesiology 1991;74:809–14.Google Scholar
  93. 93.
    Courtney A, Hauch M, Bader M, Grennan J, Hartwell B, Datta S. Perioperative analgesia with subarachnoid sufentanil administration. Reg Anesth 1992;17:274–8.Google Scholar
  94. 94.
    Vercauteren M, Lauwers E, Meert T, de Hert S, Adriaensen H. Comparison of epidural sufentanil plus clonidine with sufentanil alone for postoperative pain relief. Anaesthesia 1990;45:531–4.Google Scholar
  95. 95.
    Bach V, Carl P, Ravlo O, Crawford NE, Werner N. Potentiation of epidural opioids with epidural droperidol. Anaesthesia 1986;41:1116–9.Google Scholar
  96. 96.
    Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain 1992;48:5–12.Google Scholar
  97. 97.
    Yanez A, Sabbe MB, Stevens CW, Yaksh TL. Interaction of midazolam and morphine in the spinal cord of the rat. Neuropharmacology 1990;29:359–64.Google Scholar
  98. 98.
    Bergmans G, Vanacker B, van Aken H, Noorduin H, van Peer A, Gryseels J, et al. Investigation of the pharmacokinetics and analgesic effects of an sustained-release sufentanil for postoperative pain: an open study. J Clin Anesth 1994;6:462–8.Google Scholar
  99. 99.
    Caplan RA, Southam M. Transdermal drug delivery and its application to pain control. In: Benedetti C, Chapman CR, Giran G et al. editors Advances in pain research and therapy. New York, NY: Raven Press, 1990; 14: 233–40.Google Scholar
  100. 100.
    Lehmann KA, Zech D. Transdermal fentanyl: clinical pharmacology. J Pain Sympton Manage 1992;7(Suppl):S8-S16.Google Scholar
  101. 101.
    Payne R. Transdermal fentanyl: suggested recommendations for clinical use. J Pain Symptom Manage 1992;7(Suppl):S40-S44.Google Scholar
  102. 102.
    Hill HF. Clinical, pharmacology of transdermal fentanyl. Eur J Pain 1991;11:81–91.Google Scholar
  103. 103.
    Plezia PM, Kramer TH, Linford J, Hameroff SR. Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation. Pharmacotherapy 1989;9:2–9.Google Scholar
  104. 104.
    Ranade W. Drug delivery systems. 6. Transdermal drug delivery. J Clin Pharmacol 1991;31:401–18.Google Scholar
  105. 105.
    Singh S, Singh J. Transdermal drug delivery by passive diffusion and iontophoresis: a review. Med Res Rev 1993;13:569–621.Google Scholar
  106. 106.
    Maguire P, Tsai N, Kamal J, Cometta-Morini C, Upton C, Loew G. Pharmacological profiles of fentanyl analogs at μ δ and к opiate receptors. Eur J Pharmacol 1992;213:219–25.Google Scholar
  107. 107.
    Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993;16:1–18.Google Scholar
  108. 108.
    Ling GSF, Paul D, Simantov R, Pasternak GW. Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sci 1989;45:1627–36.Google Scholar
  109. 109.
    Paakkari P, Paakkari I, Vanhof S, Feuerstein G, Serin A-L. Dermorphin analog Tyr-D-Arg2-Phe-sarcosine-induced opioid analgesia and respiratory stimulation: the role of μ1-receptors. J Pharmacol Exp Ther 1993;266:544–50.Google Scholar
  110. 110.
    Nath C, Gupta MB, Patnaik GK, Dhawan KN. Morphineinduced Straub tail response: mediated by central μ2-opioid receptor. Eur J Pharmacol 1994;263;203–5.Google Scholar
  111. 111.
    Coccini T, Costa LG, Manzo L, Candura SM, Iapadre N, Balestra B, et al. Two subtypes of enteric non-opioid d receptors in guinea-pig cholinergic motor neurons. Eur J Pharmacol 1991;198:105–8.Google Scholar
  112. 112.
    Negri L, Potenza RL, Corsi R, Melchiorri P. Evidence for two subtypes of δ-opioid receptors in the brain. Eur J Pharmacol 1991;196:335–6.Google Scholar
  113. 113.
    Kramer TH, Davis P, Hruby VJ, Burks TF, Porreca F. In vitro potency, affinity and agonist efficacy of highly selective delta opioid receptor ligands. J Pharmacol Exp Ther 1993;266:577–84.Google Scholar
  114. 114.
    Mattia A, Farmer SC, Takemori AE, Sultana M, Portoghese PS, Mosberg HI, et al. Spinal opioid delta antinociception in the mouse: mediation by a 5′-NTII-sensitive delta receptor subtype. J Pharmacol Exp Ther 1992;260:518–25.Google Scholar
  115. 115.
    Portoghese PS, Sultana M, Nagase H, Takemori AE. A highly selective δ1-opioid receptor antagonist: 7-benzylidenenaltrexone. Eur J Pharmacol 1992;218:195–6.Google Scholar
  116. 116.
    Rothman RB, Bykov V, Jacobson AE, Rice KC, Long JE, Bowen WD. A study of the effect of the irreversible delta receptor antagonist (D-Ala2, Leu5, Cys6)-enkephalin on δcx and δncx opioid binding sites in vitro and in vivo. Peptides 1992;13:691–4.Google Scholar
  117. 117.
    Takemori AE, Portoghese PS. Enkephalin antinociception in mice is mediated by δa- and δ2-opioid receptors in the brain and spinal cord, respectively. Eur J Pharmacol 1993;242:145–50.Google Scholar
  118. 118.
    Stewart PE, Hammond DL. Evidence for delta opioid receptor subtypes in rat spinal cord: studies with intrathecal naltriben, cyclic (D-Pen2, D-Pen5)-enkephalin and (D-Ala2, Glu4)-deltorphin. J Pharmacol Exp Ther 1993;266:820–8.Google Scholar
  119. 119.
    Stewart PE, Holper EM, Hammond DL. δ-Antagonist and к-agonist activity of naltriben: evidence for differential к interaction with the δ1 and δ2 opioid receptor subtypes. Life Sci 1994;55:79–84.Google Scholar
  120. 120.
    Tseng LF, Towell JF, Fujimoto JM. Spinal release of immunoreactive met-enkephalin by intraventricular beta-endorphin and its analogs in anesthetized rats. J Pharmacol Exp Ther 1986;237:65–8.Google Scholar
  121. 121.
    Suh HH, Tseng LF, Li CH. β-Endorphin-(1–27) antagonizes β-endorphin but not morphine-, D-Pen5-enkephalin-and USO, 488H-induced analgesia in mice. Neuropharmacology 1988;27:957–61.Google Scholar
  122. 122.
    Kamei J, Iwamoto Y, Misawa M, Nagase H, Kasuya H. Antitussive effect of beta-endorphin is mediated by mu-opioid receptors, but not by kappa-or epsilon-opioid receptors. Eur J Pharmacol 1993;233:251–4.Google Scholar
  123. 123.
    Zagon IS, Gibo DM, McLaughlin PJ. Zeta (ζ), a growthrelated opioid receptor in developing rat cerebellum: identification and characterization. Brain Res 1991;551:28–35.Google Scholar
  124. 124.
    Lee NM, Smith AP. Minireview: a protein-lipid model of the opiate receptor. Life Sci 1980;26:1459–64.Google Scholar
  125. 125.
    Vaught JL, Rothman RB, Westfall TC. Mu and delta receptors: their role in analgesia and in the differential effects of opioid peptides on analgesia. Life Sci 1982;30:1443–55.Google Scholar
  126. 126.
    Porreca F, Heyman jS, Mosberg HI, Omnaas JR, Vaught JL. Role of mu and delta receptors in the supraspinal and spinal analgesic effects of (D-Pen2, D-Pen5)-enkephalin in the mouse. J Pharmacol Exp Ther 1987;241:393–400.Google Scholar
  127. 127.
    Heyman JS, Vaught JL, Mosberg HI, Haaseth RC, Porreca F. Modulation of μ-mediated antinociception by δ-agonists in the mouse: selective potentiation of morphine and normorphine by (D-Pen2, D-Pen5)-enkephalin. Eur J Pharmacol 1989;165:1–10.Google Scholar
  128. 128.
    Miaskowski C, Sutters KA, Taiwo YO, Levine JD. Antinociceptive and motor effects of delta/mu and kappa/mu combinations of intrathecal opioid agonists. Pain 1992;49:137–44.Google Scholar
  129. 129.
    Kiefel JM, Rossi GC, Bodnar RJ. Medullary μ- and δ-opioid receptors modulate mesencephalic morphine analgesia in rats. Brain Res 1993;624:151–61.Google Scholar
  130. 130.
    Adams JU, Tallarida RJ, Geller EB, Adler MW. Isobolographic superadditivity between delta and mu opioid agonists in the rat depends on the ratio of compounds, the mu agonist and the analgesic assay used. J Pharmacol Exp Ther 1993;266:1261–7.Google Scholar
  131. 131.
    Stamidis H, Young GA. Mu-delta opioid interactions I: the delta peptide, DPDPE, increases morphine-induced EEG and EEG spectral power. Peptides 1992a;13:749–53.Google Scholar
  132. 132.
    Stamidis H, Young GA. Mu-delta opioid interactions II: β-FNA inhibits DPDPE-induced increases in morphine EEG and EEG spectral power. Peptides 1992b;13:755–60.Google Scholar
  133. 133.
    Freye E, Latasch L, Portoghese PS. The delta receptor is involved in sufentanil-induced respiratory depression-opioid subreceptors mediate different effects. Eur J Anaesthesiol 1992;9:457–62.Google Scholar
  134. 134.
    Thorat SN, Reddy VPL, Bhargava HN. Biochemical and behavioral studies on the interaction between μ-and к-opiate agonists in mice. Brain Res 1993;615:191–8.Google Scholar
  135. 135.
    Garaulet JV, Laorden ML, Milanes MV. Cross-tolerance between mu-and kappa-opioid agonists in the guinea pig ileum myenteric plexus. J Pharmacol Exp Ther 1994;269:993–9.Google Scholar
  136. 136.
    Dosaka-Akita K, Tortella FC, Holaday JW, Long JB. The kappa opioid agonist U-50, 488H antagonizes respiratory effects of mu opioid receptor agonists in conscious rats. J Pharmacol Exp Ther 1993;264:631–7.Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • T. F. Meert
    • 1
  1. 1.Department of NeuropsychopharmacologyJanssen Research FoundationBeerseBelgium

Personalised recommendations