Abstract
Although it is a common practice in some centers, there is still little evidence that validates the use of topical analgesic formulations based on opioids for treatment painful skin and mucous conditions. A local focus on the analgesic treatment of painful conditions consists of applying drugs directly in the peripheral site of pain origin. This can be achieved through the topical application of a cream, lotion, gel, spray or patch for somatic sites or through the use of mouthwash in the case of lesions of the oral mucosa. These methods allow a greater local concentration of the drug at the painful site and decrease the systemic levels of the medication to minimum or negligible levels, theoretically reducing the risk of systemic adverse effects. This article aims to review relevant clinical and preclinical information on topical opioid prescribing.
References
1. World Health Organization, Pain & Policy studies Group. AMRO regional opioid consumption in Morphine equivalence. Wisconsin: University; 2011.
2. Lesniak A, Lipkowski A. Opioid peptides in peripheral pain control. Acta Neurobiol Exp. 2011;71(1):129–38.
3. Bigliardi P, Tobin D, Gaveriaux-Ruff C, Bigliardi-Qi M. Opioids and the skin--where do we stand?. Exp Dermatol. 2009;18(5):424-30.
4. Sehgal N, Smith H, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14(3)249-58.
5. Jorge L, Feres C, Teles V. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res. 2010;4:11-24.
6. McCleane G. Topical application of analgesics: a clinical option in day case anaesthesia? Curr Opin Anaesthesiol. 2010;23(6):704-7.
7. Gilson A, Ryan K, Joranson D, Dahl J. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997–2002. J. Pain Symptom Manage. 2004;28(2):176-88.
8. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers-United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487-92.
9. Galvez R. Variable use of opioid pharmacotherapy for chronic noncancer pain in Europe: causes and consequences. J Pain Palliat Care Pharmacother. 2009;23(4):346-56.
10. Stannard C. Opioid prescribing in the UK: can we avert a public health disaster?. British Journal of Pain. 2012;6(1):7-8.
11. Portenoy R. Appropriate use of opioids for persistent non-cancer pain. Lancet. 2004;364(9436):739-40.
12. Eisenberg E, McNicol E, Midbarí A. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;3:CD006146.
13. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010;363(21):1981-5.
14. Dhalla I, Mamdani M, Gomes T, Juurlink D. Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario. Can Fam Physician. 2011;57(3):e92–6.
15. Benyamin R, Trescot A, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician. 2008; 11(2):S105-20.
16. Edgerton L, Loven B. Clinical inquiries. What are the adverse effects of prolonged opioid use in patients with chronic pain?. J Fam Pract. 2011;60(5):288-9.
17. Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesth Analg. 2008;107(4): 1384-9.
18. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155(1-3): 11-7.
19. Swegle J, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347-54.
20. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5):835-42.
21. Herndon C, Jackson K, Hallin P. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy. 2002;22(2):240-50.
22. Becker D. Nausea, vomiting, and hiccups: a review of mechanisms and treatment. Anesth Prog. 2010;57(4):150-6
23. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Dermatol. 2010;35(1):2-6.
24. Cid M. Síndrome de neurotoxicidad inducido por opioides (NIO). Rev Soc Esp Dolor. 2008;15(8):521-26.
25. Byas-Smith M, Chapman S, Reed B, Cotsonis G. The effect of opioids on driving and psychomotor performance in patients with chronic pain. Clin J Pain. 2005;21(4):345-52.
26. Dimsdale J, Norman D, DeJardin D, Wallace M. The effect of opioids on sleep architecture. J Clin Sleep Med.2007;3(1):33-6.
27. Daniell H. Hypogonadism in men consuming sustained-action oral opioids. J Pain.2002;3(5):377-84.
28. Reddy R, Aung T, Karavitaki N, Wass J. Opioid induced hypogonadism. BMJ.2010;341:c4462.
29. Elliott J, Horton E, Fibuch E. The endocrine effects of long-term oral opioid therapy: a case report and review of the literature. J Opioid Manag.2011;7(2):145-54.
30. Katz N, Mazer N. The impact of opioids on the endocrine system. Clin J Pain.2009;25(2):170-5.
31. Seyfried O, Hester J. Opioids and endocrine dysfunction. British Journal of Pain.2012;6(1):17-24.
32. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician.2010;13(5):401-35.
33. Pearson E, Woosley R. QT prolongation and torsades de pointes among methadone users: Reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf.2005;14:747- 53.
34. Lee M, Silverman S, Hansen H, Patel V, Manchikant L. A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician.2011;14:145-61.
35. White F, Wilson N. Opiate-induced hypernociception and chemokine receptors. Neuropharmacology.2010;58(1):35-7.
36. Dahan A, Aarts L, Smith T. Incidence, Reversal, and Prevention of Opioid induced Respiratory Depression. Anesthesiology.2010;112(1):226-38.
37. Montandon G, Qin W, Liu H, Ren J, Greer J, Horner R. PreBotzinger Complex Neurokinin-1 Receptor-Expressing Neurons Mediate Opioid-Induced Respiratory Depression. J Neurosci.2011;31(4):1292–301.
38. Pacifici R, Patrini G, Venier I, Parolaro D, Zuccaro P, Gori E. Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates. J Pharmacol Exp Ther.1994;269:1112-6.
39. Rittner H, Roewer N, Brack A. The clinical (ir)relevance of opioid-induced immune suppression. Curr Opin Anaesthesiol.2010;23(5):588-92.
40. Jacobsen J. Topical opioids for pain #185. J Palliat Med.2009;12(4):380-1.
41. Ramesh P, Santhosh A, Kumar K. Topical morphine in Ayurveda. Palliat Med.1998;12(1):64.
42. Back I, Finlay I. Analgesic effects of topical opioids on painful skin ulcers. J Pain Symptom Manage.1995;10(7):493.
43. Zeppetella G, Joel S, Ribeiro M. Stability of morphine sulphate and diamorphine hydrochloride in intrasite gel. Palliat Med.2005;19(2):131-6.
44. Abdelmageed R, Labyad N, Watson D, Pournamdari M, Cable C, Stanley E. Evaluation of the stability of morphine sulphate in combination with Instillagel. J Clin Pharm Ther.2008;33(3):263-71.
45. Huptas L, Rompoti N, Herbig S, Körber A, Klode J, Schaderndorf D. [A new topically applied morphine gel for the pain treatment in patients with chronic leg ulcers: first results of a clinical investigation]. Hautarzt.2011;62(4):280-6.
46. Kumar R, Katare O. Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: a review. AAPS PharmSciTech.2005;6(2):298-310.
47. D’Amour F, Smith D. A method for determining loss of pain sensation. J Pharmacol Exp Ther.1941;72:74-9.
48. González-Darder J. Modelos animales de dolor y aspectos éticos de la experimentación animal. Rev Soc Esp Dolor.2000;7:313-8.
49. Kolesnikov Y, Jain S, Wilson R, Pasternak G. Peripheral morphine analgesia: synergy with central sites and a target of morphine tolerance. J Pharmacol Exp Ther.1996;279(2):502-6.
50. Kolesnikov Y, Chereshnev I, Pasternak G. Analgesic synergy between topical lidocaine and topical opioids. J Pharmacol Exp Ther.2000;295(2):546-51
51. Kolesnikov Y, Cristea M, Pasternak G. Analgesic synergy between topical morphine and butamben in mice. Anesth Analg. 2003; 97(4): 1103-7.
52. Kolesnikov Y, Oksman G, Pasternak G. Topical methadone and meperidine analgesic synergy in the mouse. Eur J Pharmacol. 2010; 638(1-3): 61-4.
53. Torres J, Carmona E, Cortés J, Guzmán C, Rocha H. Antinociceptive synergy between diclofenac and morphine after local injection into the inflamed site. Pharmacol Rep. 2013; 65(2): 358-67.
54. Rook J, Hasan W, McCarson K. Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology. 2008; 109(1):130–6.
55. Rook J, Hasan W, McCarson K. Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochem Pharmacol. 2009; 77(11): 1747-55.
56. Rook J, McCarson K. Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem Pharmacol. 2007; 74(5): p. 752-7.
57. Poonawala T, Levay-Young B, Hebbel R, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen. 2005; 13(2): 165-74.
58. Khalil Z, Helme R. Sensory peptides as neuromodulators of wound healing in aged rats. J Gerontol A Biol Sci Med Sci. 1996; 51(5): 354–61.
59. Delgado A, McManus A, Chambers J. Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. Exp Biol Med (Maywood). 2005; 230: 271–80.
60. Stein C, Küchler S. Targeting inflammation and wound healing by opioids. Trends Pharmacol Sci. 2013; 34(6): 303-312.
61. Ribeiro M, Joel S, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage. 2004; 27(5): 434–9.
62. Watterson G, Howard R, Goldman A. Peripheral opioids in inflammatory pain. Arch Dis Child. 2004; 89(7): 679-81.
63. Paice J, Von Roenn J, Hudgins J, Luong L, Krejcie T, Avram M. Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manage. 2008; 35(3): 314-20.
64. Gallagher R, Arndt D, Hunt K. Analgesic effects of topical methadone: a report of four cases. Clin J Pain. 2005; 21(2): 190-2.
65. Sylvester R, Schauer C, Thomas J, Steen P, Weisenberg A. Evaluation of methadone absorption after topical administration to hospice patients. J Pain Symptom Manage. 2011; 41(5): 828-35.
2. Lesniak A, Lipkowski A. Opioid peptides in peripheral pain control. Acta Neurobiol Exp. 2011;71(1):129–38.
3. Bigliardi P, Tobin D, Gaveriaux-Ruff C, Bigliardi-Qi M. Opioids and the skin--where do we stand?. Exp Dermatol. 2009;18(5):424-30.
4. Sehgal N, Smith H, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14(3)249-58.
5. Jorge L, Feres C, Teles V. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res. 2010;4:11-24.
6. McCleane G. Topical application of analgesics: a clinical option in day case anaesthesia? Curr Opin Anaesthesiol. 2010;23(6):704-7.
7. Gilson A, Ryan K, Joranson D, Dahl J. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997–2002. J. Pain Symptom Manage. 2004;28(2):176-88.
8. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers-United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487-92.
9. Galvez R. Variable use of opioid pharmacotherapy for chronic noncancer pain in Europe: causes and consequences. J Pain Palliat Care Pharmacother. 2009;23(4):346-56.
10. Stannard C. Opioid prescribing in the UK: can we avert a public health disaster?. British Journal of Pain. 2012;6(1):7-8.
11. Portenoy R. Appropriate use of opioids for persistent non-cancer pain. Lancet. 2004;364(9436):739-40.
12. Eisenberg E, McNicol E, Midbarí A. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;3:CD006146.
13. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010;363(21):1981-5.
14. Dhalla I, Mamdani M, Gomes T, Juurlink D. Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario. Can Fam Physician. 2011;57(3):e92–6.
15. Benyamin R, Trescot A, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician. 2008; 11(2):S105-20.
16. Edgerton L, Loven B. Clinical inquiries. What are the adverse effects of prolonged opioid use in patients with chronic pain?. J Fam Pract. 2011;60(5):288-9.
17. Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesth Analg. 2008;107(4): 1384-9.
18. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155(1-3): 11-7.
19. Swegle J, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347-54.
20. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5):835-42.
21. Herndon C, Jackson K, Hallin P. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy. 2002;22(2):240-50.
22. Becker D. Nausea, vomiting, and hiccups: a review of mechanisms and treatment. Anesth Prog. 2010;57(4):150-6
23. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Dermatol. 2010;35(1):2-6.
24. Cid M. Síndrome de neurotoxicidad inducido por opioides (NIO). Rev Soc Esp Dolor. 2008;15(8):521-26.
25. Byas-Smith M, Chapman S, Reed B, Cotsonis G. The effect of opioids on driving and psychomotor performance in patients with chronic pain. Clin J Pain. 2005;21(4):345-52.
26. Dimsdale J, Norman D, DeJardin D, Wallace M. The effect of opioids on sleep architecture. J Clin Sleep Med.2007;3(1):33-6.
27. Daniell H. Hypogonadism in men consuming sustained-action oral opioids. J Pain.2002;3(5):377-84.
28. Reddy R, Aung T, Karavitaki N, Wass J. Opioid induced hypogonadism. BMJ.2010;341:c4462.
29. Elliott J, Horton E, Fibuch E. The endocrine effects of long-term oral opioid therapy: a case report and review of the literature. J Opioid Manag.2011;7(2):145-54.
30. Katz N, Mazer N. The impact of opioids on the endocrine system. Clin J Pain.2009;25(2):170-5.
31. Seyfried O, Hester J. Opioids and endocrine dysfunction. British Journal of Pain.2012;6(1):17-24.
32. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician.2010;13(5):401-35.
33. Pearson E, Woosley R. QT prolongation and torsades de pointes among methadone users: Reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf.2005;14:747- 53.
34. Lee M, Silverman S, Hansen H, Patel V, Manchikant L. A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician.2011;14:145-61.
35. White F, Wilson N. Opiate-induced hypernociception and chemokine receptors. Neuropharmacology.2010;58(1):35-7.
36. Dahan A, Aarts L, Smith T. Incidence, Reversal, and Prevention of Opioid induced Respiratory Depression. Anesthesiology.2010;112(1):226-38.
37. Montandon G, Qin W, Liu H, Ren J, Greer J, Horner R. PreBotzinger Complex Neurokinin-1 Receptor-Expressing Neurons Mediate Opioid-Induced Respiratory Depression. J Neurosci.2011;31(4):1292–301.
38. Pacifici R, Patrini G, Venier I, Parolaro D, Zuccaro P, Gori E. Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates. J Pharmacol Exp Ther.1994;269:1112-6.
39. Rittner H, Roewer N, Brack A. The clinical (ir)relevance of opioid-induced immune suppression. Curr Opin Anaesthesiol.2010;23(5):588-92.
40. Jacobsen J. Topical opioids for pain #185. J Palliat Med.2009;12(4):380-1.
41. Ramesh P, Santhosh A, Kumar K. Topical morphine in Ayurveda. Palliat Med.1998;12(1):64.
42. Back I, Finlay I. Analgesic effects of topical opioids on painful skin ulcers. J Pain Symptom Manage.1995;10(7):493.
43. Zeppetella G, Joel S, Ribeiro M. Stability of morphine sulphate and diamorphine hydrochloride in intrasite gel. Palliat Med.2005;19(2):131-6.
44. Abdelmageed R, Labyad N, Watson D, Pournamdari M, Cable C, Stanley E. Evaluation of the stability of morphine sulphate in combination with Instillagel. J Clin Pharm Ther.2008;33(3):263-71.
45. Huptas L, Rompoti N, Herbig S, Körber A, Klode J, Schaderndorf D. [A new topically applied morphine gel for the pain treatment in patients with chronic leg ulcers: first results of a clinical investigation]. Hautarzt.2011;62(4):280-6.
46. Kumar R, Katare O. Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: a review. AAPS PharmSciTech.2005;6(2):298-310.
47. D’Amour F, Smith D. A method for determining loss of pain sensation. J Pharmacol Exp Ther.1941;72:74-9.
48. González-Darder J. Modelos animales de dolor y aspectos éticos de la experimentación animal. Rev Soc Esp Dolor.2000;7:313-8.
49. Kolesnikov Y, Jain S, Wilson R, Pasternak G. Peripheral morphine analgesia: synergy with central sites and a target of morphine tolerance. J Pharmacol Exp Ther.1996;279(2):502-6.
50. Kolesnikov Y, Chereshnev I, Pasternak G. Analgesic synergy between topical lidocaine and topical opioids. J Pharmacol Exp Ther.2000;295(2):546-51
51. Kolesnikov Y, Cristea M, Pasternak G. Analgesic synergy between topical morphine and butamben in mice. Anesth Analg. 2003; 97(4): 1103-7.
52. Kolesnikov Y, Oksman G, Pasternak G. Topical methadone and meperidine analgesic synergy in the mouse. Eur J Pharmacol. 2010; 638(1-3): 61-4.
53. Torres J, Carmona E, Cortés J, Guzmán C, Rocha H. Antinociceptive synergy between diclofenac and morphine after local injection into the inflamed site. Pharmacol Rep. 2013; 65(2): 358-67.
54. Rook J, Hasan W, McCarson K. Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology. 2008; 109(1):130–6.
55. Rook J, Hasan W, McCarson K. Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochem Pharmacol. 2009; 77(11): 1747-55.
56. Rook J, McCarson K. Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem Pharmacol. 2007; 74(5): p. 752-7.
57. Poonawala T, Levay-Young B, Hebbel R, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen. 2005; 13(2): 165-74.
58. Khalil Z, Helme R. Sensory peptides as neuromodulators of wound healing in aged rats. J Gerontol A Biol Sci Med Sci. 1996; 51(5): 354–61.
59. Delgado A, McManus A, Chambers J. Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. Exp Biol Med (Maywood). 2005; 230: 271–80.
60. Stein C, Küchler S. Targeting inflammation and wound healing by opioids. Trends Pharmacol Sci. 2013; 34(6): 303-312.
61. Ribeiro M, Joel S, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage. 2004; 27(5): 434–9.
62. Watterson G, Howard R, Goldman A. Peripheral opioids in inflammatory pain. Arch Dis Child. 2004; 89(7): 679-81.
63. Paice J, Von Roenn J, Hudgins J, Luong L, Krejcie T, Avram M. Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manage. 2008; 35(3): 314-20.
64. Gallagher R, Arndt D, Hunt K. Analgesic effects of topical methadone: a report of four cases. Clin J Pain. 2005; 21(2): 190-2.
65. Sylvester R, Schauer C, Thomas J, Steen P, Weisenberg A. Evaluation of methadone absorption after topical administration to hospice patients. J Pain Symptom Manage. 2011; 41(5): 828-35.
Downloads
Download data is not yet available.