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Opioid analgesic

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Opioid analgesics, also called narcotics, are drugs usually used for treating pain. Opioid analgesics are defined as "all of the natural and semisynthetic alkaloid derivatives from opium, their pharmacologically similar synthetic surrogates, as well as all other compounds whose opioid-like actions are blocked by the nonselective opioid receptor antagonist naloxone.[1]

Pharmacology[edit]

There a several opioid receptors. All are G-protein-coupled cell surface receptors. Clinically useful analgesic families vary in their receptor effects; they range from pure agonists of all receptor types, to selective agonists, to agonist-antagonists.

Metabolism[edit]

Some opioids are metabolized by cytochrome P-450 and cytochrome P-450 CYP2D6.[2] [3][4]

Reduced metabolizers of codeine, tramadol, oxycodone, hydrocodone may have reduced effect due to decreased conversion to morphine.[2]

Ultrarapid metabolizers of codeine[5], oxycodone, and hydrocodone may have increased drug toxicity due to increased conversion to morphine.[2]

Available opioid analgesics[edit]

Current opioid analgesics are below [6]

Tables of morphine equivalent daily dose and IV to PO conversion are available to help dosing, although direct conversion is unwise with opioids with complex pharmacodynamics, such as methadone.

A number of oral forms are combined with acetaminophen to reduce the possibility of diversion to injected abuse, although acetaminophen also has a distinct and potentially synergistic analgesic effect. Acetaminophen has been found to be more toxic, with or without opioids, than had been generally believed, and the FDA has recommended restrictions on its uses.[7][6] The American Pain Foundation is concerned that these recommendations consider the matter carefully, lest there be undertreatment with appropriate opioids. [8] Combination with aspirin and other non-narcotic agents was common before the widespread use of acetaminophen

Selected opioids[9]
Specific drug Potency relative to oral morphine[10] Chemical class Receptor action Metabolism[11][12] Comments
Naturally occurring opium alkaloids
Morphine 1 morphine mu, kappa (weak)
Codeine 0.15 codeine mu (partial agonist) Good oral absorption
Semi-synthetic opioids
Diacetylmorphine (heroin) 1 morphine mu, kappa (weak) Faster blood-brain transfer than morphine but both produce the same primary active metabolite (morphine prodrug)
Hydrocodone 1 thebaine/codeine mu (partial)
Oxycodone 1.5 thebaine/codeine mu (partial) Oxycodone may increase mortality relative to codeine and hydrocodone[13] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[13]
Hydromorphone (Dilaudid) 4 thebaine mu Mostly hepatic Oral bioavailability is approximately 24%[14]
Buprenorphine thebaine mu, antagonist of delta and kappa
Fully synthetic opioids
Meperidine 0.1 Meperidine mu Good oral absorption; toxic metabolite accumulates on prolonged use
Fentanyl 2.4 Meperidine mu Transdermal and transmucosal absorption
Remifentanil Meperidine mu
Methadone 3 methadone mu Good oral absorption. Bioavailability of methadone ranges between 36 to 100%.[15] Different half-lives for analgesia and for blocking withdrawal
Tramadol 0.1 tramadol mu Also inhibits monoamine oxidase; can raise norepinephrine and serotonin, and cause serotonin syndrome
Propoxyphene 0.23 propoxyphene mu L-isomer is antitussive; analgesic D-isomer was removed from the U.S. market as too risky for its limited effectiveness.[16]

Effectiveness[edit]

Opioids are commonly prescribed for pain, and their usage may be increasing.[17] In emergency rooms, non-Hispanic white patients are more likely to receive narcotics than patients of other ethnicities.[17]

Opioids are effective for short term use (1-16 weeks)[18].

Chronic benign pain[edit]

For chronic, non-cancer pain, opioids may give short term reduction in pain compared to placebo.[19][20][21]

The role of long term treatment of chronic non-cancer pain is not clear.

One systematic review found that trials of short term opioids did not improve functional status compared to placebo in chronic pain.[19] However, a second systematic review, found that opioids improved functional status compared to placebo, but not compared to other drugs.[21]

As example randomized controlled trials, opioids reduced pain in the short term, but did not improve function in comparison to an cholinergic antagonist placebo[24] or tricyclic antidepressant.[25]

Most trials are funded by industry.[21]

Administration[edit]

Clinical practice guidelines are available.[26]

Tables of morphine equivalent daily dose and IV to PO conversion are available to help dosing, but must be used with caution. Some opioids, such as methadone, do not lend themselves to simple conversion due to greatly differing half-lives. While an antagonist or partial antagonist may have equianalgesic dosing in an opioid-naive patient, switching from, for example, long-term morphine to buprenorphine can cause withdrawal.

Routes of administration[edit]

Most opioids can be administered parenterally. Recent developments have provided alternate formulation that improve oral effectiveness of drugs historically injected, such as morphine.

Novel routes are being found effective, such as transdermal skin patches that provide a constant low-rate dose, and transmucosal and intranasal routes for quick action.

Chronic use[edit]

Fear of addiction had long interfered with the extended use of opioids even in terminal patients. Current practice, however, includes the indefinite use of opioids in nonterminal patients with pain that can only be controlled by opioids. The World Health Organization, for example, has a "pain pyramid" for rheumatic disease, which begins with acetaminophen or equivalents, and moves to increasingly powerful opioids. Long-term opioid therapy is prescribed both for analgesia, and also the treatment of opioid dependence.

Mortality may be increased upon both starting and topic opioid maintenance.[27]

Advice for using administering chronic narcotics[26] and for treating acute pain among patients on chronic methadone is available[28]. Special technique may also be needed for patients receiving buprenorphine for chronic pain.

There are challenges in prescribing opioids with specialized actions, such as partial agonists and mixed agonist/antagonists. These may interfere with the effectiveness of breakthrough medications for additional acute pain. Such drugs also may be ineffective or produce withdrawal in patients receiving other long-term opioids.

Monitoring chronic use[edit]

Appropriate use may be improved with prescription-drug monitoring programs in which prescribers can track all opioid prescriptions for a patient. In the United States of America, the U.S. Department of Justice's Drug Enforcement Administration coordinates the State Prescription Drug Monitoring Programs. Prescription-drug monitoring programs have been studied for the Ohio Automated Rx Reporting System (OARRS).[29] Two additional systems under development are bu the United States Department of Health and Human Services and one by the Department of Justice.[30]

Opioid treatment agreements and urine drug testing may reduce opioid misuse by patients with chronic pain. [31] Urine drug testing is of two types:[32]

Adverse effects[edit]

Opioid analgesics may cause more drug toxicity, at least in geriatrics, than non-selective inhibitors of cyclooxygenase (non-steroidal anti-inflammatory agents) or cyclooxygenase 2 inhibitors.[33]

Oxycodone and codeine may increase mortality relative to codeine and hydrocodone[13] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[13] In contrast to hydrocodone, oxycodone and codeine and metabolized by cytochrome P-450 CYP2D6 which may lead to variable pharmacokinetics due to single-nucleotide polymorphisms and drug interactions.[34]

Opioid analgesics, with long-term use, 80% of patients may have drug toxicity, most commonly gastrointestinal. In addition, substance abuse and "aberrant medication-taking behaviors" may occur.[20]

Serious drug toxicity from long-term use may be low according to one systematic review.[22]

Constipation[edit]

Constipation may be reduced by methylnaltrexone, a mu-opioid receptor antagonist. In a randomized controlled trial of patients with advanced illness, 48% of patients receiving methylnaltrexone had a bowel movement compared to 15% of patients received placebo (number needed to treat = 3.0. Click here to adjust these results for patients at higher or lower risk.)[35] Although mu-receptors provide analgesia, methylnaltrexone is a charged quaternary amine so that it does not well cross the blood-brain barrier. Methylnaltrexone can also help patients taking chronic opiates for non-malingnant pain.[36]

Dietary agents and inert physical agents may help. A high-fiber diet is desirable, possibly with fiber supplements such as psyllium and metacellulose. The stool softener docusate is often prescribed. Stronger laxatives are not desirable.

Male hypogonadism[edit]

Chronic opioids may cause male hypogonadism.[37][38]

Employability[edit]

Use of opioids may be a risk factor for failing to return to work.[39][40]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.[41]

Impaired judgment[edit]

Opioids may increase risk of traffic accidents[42] and accidental falls[43].

Dependency[edit]

For more information, see: Opiate dependence.

Opioid agonist therapy includes buprenorphine and methadone. Although buprenorphine–naloxone may be less effective than methadone[44], it has more predictable dosing[45], and can be prescribed by qualifying office-based physicians.[46]

Mortality and Overdose[edit]

Number of Poisoning Deaths Involving Opioid Analgesics and Other Drugs or Substances --- United States, 1999--2007.

Death from overdose on opioids may be more common than traffic accidents in the United States.[47] The rate of overdose is increasing faster among women and men according to the Centers for Disease Controll.[48]

Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.[49]

Overdose may be more common with with doses equivalent to more than 100 mg/day of morphine.[50] Overdose may[51] or may not[50] be increased with long acting opioids.

In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.[52]

Substance abuse[edit]

With chronic use for treatment of pain, dependency may lead to substance abuse and "aberrant medication-taking behaviors" may occur.[20] From 2000-2005, the abuse of prescribed opiods, especially oxycodone extended release (OxyContin) and hydrocodone, has increased.[53] From Contracts may reduce abuse, but comparative studies provide conflicting results.[54] Most agreements stated, "patients agreed not to abuse illicit drugs or alcohol, obtain opioids from more than 1 provider or pharmacy, or request a refill before the previous prescription should have been completed."

Withdrawal[edit]

Adding narcotic antagonists combined with alpha-adrenergic agonists may reduce withdrawal symptoms.[55]

Tolerance[edit]

N-methyl-d-aspartate receptor (NMDA) activation may lead to neuropathic pain and tolerance.[56][57] Methadone, which is a NMDA antagonist, may reduce tolerance.

Pruritis[edit]

Pruritis from histamine release may occur.[58] Anecdotally, one of the reason for using antihistamines as adjuvants, such as hydroxyzine and promethazine, are to alleviate some of these side effects, as well as nausea. The less sedating hydroxyzine also may potentiate analgesia and have a better antipruritic effect although promethazine may be stronger against nausea.

References[edit]

  1. ↑ Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical Publishing Division, 512. ISBN 0-07-145153-6. 
  2. ↑ 2.0 2.1 2.2 Reynolds KK, Ramey-Hartung B, Jortani SA (2008). "The value of CYP2D6 and OPRM1 pharmacogenetic testing for opioid therapy.". Clin Lab Med 28 (4): 581-98. DOI:10.1016/j.cll.2008.10.003. PMID 19059064. Research Blogging.
  3. ↑ Stamer UM, Zhang L, Stüber F (2010). "Personalized therapy in pain management: where do we stand?". Pharmacogenomics 11 (6): 843-64. DOI:10.2217/pgs.10.47. PMID 20504256. Research Blogging.
  4. ↑ http://pubmed.gov/
  5. ↑ Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G (2009). "Codeine, ultrarapid-metabolism genotype, and postoperative death.". N Engl J Med 361 (8): 827-8. DOI:10.1056/NEJMc0904266. PMID 19692698. Research Blogging.
  6. ↑ 6.0 6.1 (2003) “78. Management of Cancer Pain”, Cancer medicine 6. Hamilton, Ont.: BC Decker. ISBN 1-55009-213-8. 
  7. ↑ Joint Meeting of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), June 29-30, 2009
  8. ↑ American Pain Foundation shares Acetaminophen Task Force's Concerns over Recent FDA Advisory Committee Recommendations Regarding Prescription Acetaminophen/Opioid Combination, American Pain Foundation
  9. ↑ Masters, Susan B.; Katzung, Bertram G.; Trevor, Anthony J. (2009). “Basic Pharmacology of the Opioid Analgesics”, Basic and Clinical Pharmacology, 11th. New York: McGraw-Hill Medical. ISBN 0-07-160405-7.  (Condensed from Table 31-2
  10. ↑ Korff MV, Saunders K, Thomas Ray G, Boudreau D, Campbell C, Merrill J et al. (2008). "De facto long-term opioid therapy for noncancer pain.". Clin J Pain 24 (6): 521-7. DOI:10.1097/AJP.0b013e318169d03b. PMID 18574361. Research Blogging.
  11. ↑ Davies G, Kingswood C, Street M (1996). "Pharmacokinetics of opioids in renal dysfunction.". Clin Pharmacokinet 31 (6): 410-22. PMID 8968655.
  12. ↑ Conway BR, Fogarty DG, Nelson WE, Doherty CC (2006). "Opiate toxicity in patients with renal failure.". BMJ 332 (7537): 345-6. DOI:10.1136/bmj.332.7537.345. PMID 16470057. PMC PMC1363915. Research Blogging.
  13. ↑ 13.0 13.1 13.2 13.3 Solomon DH, Rassen JA, Glynn RJ, Garneau K, Levin R, Lee J et al. (2010). "The comparative safety of opioids for nonmalignant pain in older adults.". Arch Intern Med 170 (22): 1979-86. DOI:10.1001/archinternmed.2010.450. PMID 21149754. Research Blogging.
  14. ↑ Hydromorphone - FDA approved drug information (drug label) from DailyMed (U.S. National Library of Medicine).
  15. ↑ Methadone - FDA approved drug information (drug label) from DailyMed (U.S. National Library of Medicine).
  16. ↑ Allison Gandey (19 November 2010), "Propoxyphene Withdrawn From US Market", Medscape Medical News
  17. ↑ 17.0 17.1 Pletcher MJ, Kertesz SG, Kohn MA, Gonzales R (2008). "Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments". JAMA 299 (1): 70–8. DOI:10.1001/jama.2007.64. PMID 18167408. Research Blogging.
  18. ↑ Chou R, Huffman LH, American Pain Society. American College of Physicians (2007). "Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline.". Ann Intern Med 147 (7): 505-14. PMID 17909211. [e] Review in: Evid Based Nurs. 2008 Apr;11(2):50
  19. ↑ 19.0 19.1 Kalso E, Edwards JE, Moore RA, McQuay HJ (2004). "Opioids in chronic non-cancer pain: systematic review of efficacy and safety". Pain 112 (3): 372–80. DOI:10.1016/j.pain.2004.09.019. PMID 15561393. Research Blogging.
  20. ↑ 20.0 20.1 20.2 Martell BA, O'Connor PG, Kerns RD, Becker WC, Morales KH, Kosten TR et al. (2007). "Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction.". Ann Intern Med 146 (2): 116-27. PMID 17227935.
  21. ↑ 21.0 21.1 21.2 Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E (2006). "Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects". CMAJ 174 (11): 1589–94. DOI:10.1503/cmaj.051528. PMID 16717269. Research Blogging.
  22. ↑ 22.0 22.1 Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C et al. (2010). "Long-term opioid management for chronic noncancer pain.". Cochrane Database Syst Rev (1): CD006605. DOI:10.1002/14651858.CD006605.pub2. PMID 20091598. Research Blogging.
  23. ↑ Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik JG, Blazina I, Dana T, Bougatsos C, Turner J. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence Report/Technology Assessment No. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence Report/Technology Assessment No. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014.
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  25. ↑ Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S et al. (2002). "Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.". Neurology 59 (7): 1015-21. PMID 12370455. [e] Review in: J Fam Pract. 2003 Jul;52(7):517-8
  26. ↑ 26.0 26.1 Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P et al. (2009). "Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.". J Pain 10 (2): 113-30. DOI:10.1016/j.jpain.2008.10.008. PMID 19187889. Research Blogging.
  27. ↑ Cornish R et al. (2010) Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database. BMJ 2010; 341:c5475 DOI:10.1136/bmj.c5475
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  29. ↑ Baehren DF, Marco CA, Droz DE, Sinha S, Callan EM, Akpunonu P (2010). "A statewide prescription monitoring program affects emergency department prescribing behaviors.". Ann Emerg Med 56 (1): 19-23.e1-3. DOI:10.1016/j.annemergmed.2009.12.011. PMID 20045578. Research Blogging.
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  31. ↑ Starrels JL, Becker WC, Alford DP, Kapoor A, Williams AR, Turner BJ (2010). "Systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain.". Ann Intern Med 152 (11): 712-20. DOI:10.1059/0003-4819-152-11-201006010-00004. PMID 20513829. Research Blogging.
  32. ↑ Tenore PL (October 2010). "Advanced urine toxicology testing". J Addict Dis 29 (4): 436–48. DOI:10.1080/10550887.2010.509277. PMID 20924879. Research Blogging.
  33. ↑ Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, Schneeweiss S (2010). "The comparative safety of analgesics in older adults with arthritis.". Arch Intern Med 170 (22): 1968-76. DOI:10.1001/archinternmed.2010.391. PMID 21149752. Research Blogging.
  34. ↑ Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC et al. (2010). "Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.". Br J Pharmacol 160 (4): 919-30. DOI:10.1111/j.1476-5381.2010.00709.x. PMID 20590588. PMC PMC2935998. Research Blogging.
  35. ↑ 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 May 29;358(22):2332-43. PMID 18509120
  36. ↑ Michna E, Blonsky ER, Schulman S, Tzanis E, Manley A, Zhang H et al. (2011). "Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.". J Pain 12 (5): 554-62. DOI:10.1016/j.jpain.2010.11.008. PMID 21429809. Research Blogging.
  37. ↑ Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT (2000). "Hypogonadism in patients treated with intrathecal morphine.". Clin J Pain 16 (3): 251-4. PMID 11014399. [e]
  38. ↑ Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D (2005). "Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence.". J Clin Endocrinol Metab 90 (1): 203-6. DOI:10.1210/jc.2004-0929. PMID 15483091. Research Blogging.
  39. ↑ Brede E, Mayer TG, Gatchel RJ (2012). "Prediction of failure to retain work 1 year after interdisciplinary functional restoration in occupational injuries.". Arch Phys Med Rehabil 93 (2): 268-74. DOI:10.1016/j.apmr.2011.08.029. PMID 22289236. Research Blogging.
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  41. ↑ White KT, Dillingham TR, González-Fernández M, Rothfield L (2009). "Opiates for chronic nonmalignant pain syndromes: can appropriate candidates be identified for outpatient clinic management?". Am J Phys Med Rehabil 88 (12): 995-1001. DOI:10.1097/PHM.0b013e3181bc006e. PMID 19789432. Research Blogging.
  42. ↑ Orriols L, Delorme B, Gadegbeku B, Tricotel A, Contrand B, et al. 2010 Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study. PLoS Med 7(11): e1000366. DOI:10.1371/journal.pmed.1000366
  43. ↑ Miller M, Stürmer T, Azrael D, Levin R, Solomon DH (2011). "Opioid analgesics and the risk of fractures in older adults with arthritis.". J Am Geriatr Soc 59 (3): 430-8. DOI:10.1111/j.1532-5415.2011.03318.x. PMID 21391934. Research Blogging.
  44. ↑ Schottenfeld RS, Chawarski MC, Pakes JR, Pantalon MV, Carroll KM, Kosten TR (2005). "Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence.". Am J Psychiatry 162 (2): 340-9. DOI:10.1176/appi.ajp.162.2.340. PMID 15677600. Research Blogging. Review in: Evid Based Ment Health. 2005 Nov;8(4):112>
  45. ↑ Simoens S, Matheson C, Bond C, Inkster K, Ludbrook A (2005). "The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence.". Br J Gen Pract 55 (511): 139-46. PMID 15720937. PMC PMC1463190.
  46. ↑ Sullivan LE, Fiellin DA (2008). "Narrative review: buprenorphine for opioid-dependent patients in office practice.". Ann Intern Med 148 (9): 662-70. PMID 18458279.
  47. ↑ Template:Err. Drug deaths now outnumber traffic fatalities in U.S., Times analysis shows - latimes.com, Los Angeles Times, Tribune Co, Template:Err. Retrieved on September 23, 2011.
  48. ↑ Centers for Disease Control and Prevention (CDC) (2013). "Vital signs: overdoses of prescription opioid pain relievers and other drugs among women - United States, 1999-2010.". MMWR Morb Mortal Wkly Rep 62 (26): 537-42. PMID 23820967. [e]
  49. ↑ Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD et al. (2010). "Opioid prescriptions for chronic pain and overdose: a cohort study.". Ann Intern Med 152 (2): 85-92. DOI:10.1059/0003-4819-152-2-201001190-00006. PMID 20083827. Research Blogging.
  50. ↑ 50.0 50.1 Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA et al. (2011). "Association between opioid prescribing patterns and opioid overdose-related deaths.". JAMA 305 (13): 1315-21. DOI:10.1001/jama.2011.370. PMID 21467284. Research Blogging.
  51. ↑ Braden JB, Russo J, Fan MY, Edlund MJ, Martin BC, DeVries A et al. (2010). "Emergency department visits among recipients of chronic opioid therapy.". Arch Intern Med 170 (16): 1425-32. DOI:10.1001/archinternmed.2010.273. PMID 20837827. Research Blogging.
  52. ↑ need to dig up the Cornell handbook
  53. ↑ Cicero TJ, Inciardi JA, Muñoz A (2005). "Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004.". J Pain 6 (10): 662-72. DOI:10.1016/j.jpain.2005.05.004. PMID 16202959. Research Blogging.
  54. ↑ Starrels, Joanna L.; William C. Becker, Daniel P. Alford, Alok Kapoor, Arthur Robinson Williams, Barbara J. Turner (2010-06-01). "Systematic Review: Treatment Agreements and Urine Drug Testing to Reduce Opioid Misuse in Patients With Chronic Pain". Annals of Internal Medicine 152 (11 pages = 712-720). DOI:10.1059/0003-4819-152-11-201006010-00004. Retrieved on 2010-06-01. Research Blogging.
  55. ↑ Gowing L, Ali R, White JM (2009). "Opioid antagonists with minimal sedation for opioid withdrawal.". Cochrane Database Syst Rev (4): CD002021. DOI:10.1002/14651858.CD002021.pub3. PMID 19821290. Research Blogging.
  56. ↑ Trujillo KA, Akil H (1991). "Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801.". Science 251 (4989): 85-7. PMID 1824728.
  57. ↑ Prommer E (2006). "Rotating methadone to other opioids: a lesson in the mechanisms of opioid tolerance and opioid-induced pain.". J Palliat Med 9 (2): 488-93. DOI:10.1089/jpm.2006.9.488. PMID 16629581. Research Blogging.
  58. ↑ Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H et al. (2001). "Strategies to manage the adverse effects of oral morphine: an evidence-based report.". J Clin Oncol 19 (9): 2542-54. PMID 11331334.

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