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These include: dose-related respiratory depression (see below), confusion, hallucinations, [[delirium]], [[urticaria]], [[hypothermia]], [[bradycardia]]/[[tachycardia]], [[orthostatic hypotension]], dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil).
These include: dose-related respiratory depression (see below), confusion, hallucinations, [[delirium]], [[urticaria]], [[hypothermia]], [[bradycardia]]/[[tachycardia]], [[orthostatic hypotension]], dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil).
===Gastroparesis===
Opioid use may be associated with gastroparesis<ref name="pmid28529168">{{cite journal| author=Camilleri M, Lembo A, Katzka DA| title=Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits. | journal=Clin Gastroenterol Hepatol | year= 2017 | volume= 15 | issue= 9 | pages= 1338-1349 | pmid=28529168 | doi=10.1016/j.cgh.2017.05.014 | pmc=5565678 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529168  }} </ref>, possibly via stimulation of μ (MOP; β-endorphin) and maybe δ (DOP; enkephalin) receptors.
Codeine may be more likely to affect the gastrointestinal tract<ref name="pmid23788866">{{cite journal| author=Leppert W| title=The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities. | journal=Contemp Oncol (Pozn) | year= 2012 | volume= 16 | issue= 2 | pages= 125-31 | pmid=23788866 | doi=10.5114/wo.2012.28792 | pmc=3687404 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23788866  }} </ref>.
[[Buprenorphine]], a partial agonist at the μ receptor, has also been reported to cause gastroparesis<ref name="pmid17298658">{{cite journal| author=Jakobovits SL, McDonough M, Chen RY| title=Buprenorphine-associated gastroparesis during in-patient heroin detoxification. | journal=Addiction | year= 2007 | volume= 102 | issue= 3 | pages= 490-1 | pmid=17298658 | doi=10.1111/j.1360-0443.2006.01684.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17298658  }} </ref>.
The affect of tramadol is not clear<ref name="pmid8965152">{{cite journal| author=Maurer AH, Krevsky B, Knight LC, Brown K| title=Opioid and opioid-like drug effects on whole-gut transit measured by scintigraphy. | journal=J Nucl Med | year= 1996 | volume= 37 | issue= 5 | pages= 818-22 | pmid=8965152 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8965152  }} </ref>.
Treatment may include sympatholyic medications such as acute phentolamine or chronic clonidine<ref name="pmid17003080">{{cite journal| author=Phillips WJ, Tollefson B, Johnson A, Abell T, Lerant A| title=Relief of acute pain in chronic idiopathic gastroparesis with intravenous phentolamine. | journal=Ann Pharmacother | year= 2006 | volume= 40 | issue= 11 | pages= 2032-6 | pmid=17003080 | doi=10.1345/aph.1H255 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17003080  }} </ref>.


===Male hypogonadism===
===Male hypogonadism===
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Opioids may increase risk of [[traffic accident]]s<ref>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}}  </ref> and [[accidental fall]]s<ref name="pmid21391934">{{cite journal| author=Miller M, Stürmer T, Azrael D, Levin R, Solomon DH| title=Opioid analgesics and the risk of fractures in older adults with arthritis. | journal=J Am Geriatr Soc | year= 2011 | volume= 59 | issue= 3 | pages= 430-8 | pmid=21391934 | doi=10.1111/j.1532-5415.2011.03318.x | pmc= | url= }} </ref>.
Opioids may increase risk of [[traffic accident]]s<ref>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}}  </ref> and [[accidental fall]]s<ref name="pmid21391934">{{cite journal| author=Miller M, Stürmer T, Azrael D, Levin R, Solomon DH| title=Opioid analgesics and the risk of fractures in older adults with arthritis. | journal=J Am Geriatr Soc | year= 2011 | volume= 59 | issue= 3 | pages= 430-8 | pmid=21391934 | doi=10.1111/j.1532-5415.2011.03318.x | pmc= | url= }} </ref>.


===Dependency===
===Opioid Induced Hyperalgesia===
Opioid agonist therapy includes [[buprenorphine]] and [[methadone]]. Although [[buprenorphine]]–[[naloxone]] may be less effective than [[methadone]]<ref name="pmid15677600">{{cite journal| author=Schottenfeld RS, Chawarski MC, Pakes JR, Pantalon MV, Carroll KM, Kosten TR| title=Methadone versus buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. | journal=Am J Psychiatry | year= 2005 | volume= 162 | issue= 2 | pages= 340-9 | pmid=15677600
[[Opioid-induced hyperalgesia]] is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. [[Opioid-induced hyperalgesia]] has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some [[palliative care]] patients, most often when dose is escalated rapidly. <ref>Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." ''Am J Hosp Palliat Care''. 2003 Nov-Dec;20(6):459-61. PMID 14649563</ref> <ref>Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." ''J Pain Palliat Care Pharmacother''. 2007;21(1):15-25. PMID 17430825</ref> If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. <ref>Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." ''Am J Hosp Palliat Care''. 2005 Jul-Aug;22(4):291-4. Review. PMID 16082916 </ref> <ref>Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." ''J Pain Palliat Care Pharmacother''. 2004;18(3):75-9. Review. PMID 15364634 </ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15677600 | doi=10.1176/appi.ajp.162.2.340 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16246888 Review in: Evid Based Ment Health. 2005 Nov;8(4):112]></ref>, it has more predictable dosing<ref name="pmid15720937">{{cite journal| author=Simoens S, Matheson C, Bond C, Inkster K, Ludbrook A| title=The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. | journal=Br J Gen Pract | year= 2005 | volume= 55 | issue= 511 | pages= 139-46 | pmid=15720937
 
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15720937 | pmc=PMC1463190 }}</ref>, and can be prescribed by qualifying office-based physicians.<ref name="pmid18458279">{{cite journal| author=Sullivan LE, Fiellin DA| title=Narrative review: buprenorphine for opioid-dependent patients in office practice. | journal=Ann Intern Med | year= 2008 | volume= 148 | issue= 9 | pages= 662-70 | pmid=18458279
===Sleep disorders===
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18458279 }}</ref>
In a small study of patients on chronic opioids, about half had sleep disorders<ref name="pmid25126029">{{cite journal| author=Rose AR, Catcheside PG, McEvoy RD, Paul D, Kapur D, Peak E | display-authors=etal| title=Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. | journal=J Clin Sleep Med | year= 2014 | volume= 10 | issue= 8 | pages= 847-52 | pmid=25126029 | doi=10.5664/jcsm.3950 | pmc=4106937 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25126029  }} </ref>:
* daytime hypercapnia
* average [[apnea-hypopnea index]] (AHI) 33


====Mortality and Overdose====
====Mortality and Overdose====
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In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.<ref>''need to dig up the Cornell handbook''</ref>
In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.<ref>''need to dig up the Cornell handbook''</ref>


====Substance abuse====
===Other adverse effects===
With chronic use for treatment of [[pain]], [[dependency]] may lead to substance abuse and "aberrant medication-taking behaviors" may occur.<ref name="pmid17227935">{{cite journal |author=Martell BA, O'Connor PG, Kerns RD, ''et al'' |title=Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction |journal=Ann. Intern. Med. |volume=146 |issue=2 |pages=116–27 |year=2007 |pmid=17227935 |doi= |url=http://www.annals.org/cgi/content/full/146/2/116 |issn=}}</ref> From 2000-2005, the abuse of prescribed opiods, especially [[oxycodone|oxycodone extended release (OxyContin)]] and [[hydrocodone]], has increased.<ref name="pmid16202959">{{cite journal| author=Cicero TJ, Inciardi JA, Muñoz A| title=Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004. | journal=J Pain | year= 2005 | volume= 6 | issue= 10 | pages= 662-72 | pmid=16202959 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16202959 | doi=10.1016/j.jpain.2005.05.004 }} </ref> From Contracts may reduce abuse, but comparative studies provide conflicting results.<ref>{{Cite journal | doi = 10.1059/0003-4819-152-11-201006010-00004 | volume = 152 | issue = 11  pages = 712-720 | last = Starrels | first = Joanna L. | coauthors = William C. Becker, Daniel P. Alford, Alok Kapoor, Arthur Robinson Williams, Barbara J. Turner | title = Systematic Review: Treatment Agreements and Urine Drug Testing to Reduce Opioid Misuse in Patients With Chronic Pain | journal = Annals of Internal Medicine | accessdate = 2010-06-01 | date = 2010-06-01 | url = http://www.annals.org/content/152/11/712.abstract }}</ref> 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."
 
 
 
===Other adverse effects:===
 
[[Opioid-induced hyperalgesia]] has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some [[palliative care]] patients, most often when dose is escalated rapidly. <ref>Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." ''Am J Hosp Palliat Care''. 2003 Nov-Dec;20(6):459-61. PMID 14649563</ref> <ref>Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." ''J Pain Palliat Care Pharmacother''. 2007;21(1):15-25. PMID 17430825</ref> If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. <ref>Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." ''Am J Hosp Palliat Care''. 2005 Jul-Aug;22(4):291-4. Review. PMID 16082916 </ref> <ref>Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." ''J Pain Palliat Care Pharmacother''. 2004;18(3):75-9. Review. PMID 15364634 </ref>


Both therapeutic and chronic use of opioids can compromise the function of the [[immune system]].  Opioids decrease the proliferation of [[macrophage]] progenitor cells and [[lymphocyte]]s, and affect cell differentiation (Roy & Loh, 1996).  Opioids may also inhibit [[leukocyte]] migration.  However the relevance of this in the context of pain relief is not known.
Both therapeutic and chronic use of opioids can compromise the function of the [[immune system]].  Opioids decrease the proliferation of [[macrophage]] progenitor cells and [[lymphocyte]]s, and affect cell differentiation (Roy & Loh, 1996).  Opioids may also inhibit [[leukocyte]] migration.  However the relevance of this in the context of pain relief is not known.
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* When discontinuing opioids in tolerant users, a taper of [[buprenorphine]] over 4 weeks may be used.<ref name="pmid24153411">{{cite journal| author=Sigmon SC, Dunn KE, Saulsgiver K, Patrick ME, Badger GJ, Heil SH et al.| title=A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. | journal=JAMA Psychiatry | year= 2013 | volume= 70 | issue= 12 | pages= 1347-54 | pmid=24153411 | doi=10.1001/jamapsychiatry.2013.2216 | pmc=PMC4131728 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24153411  }} </ref>
* When discontinuing opioids in tolerant users, a taper of [[buprenorphine]] over 4 weeks may be used.<ref name="pmid24153411">{{cite journal| author=Sigmon SC, Dunn KE, Saulsgiver K, Patrick ME, Badger GJ, Heil SH et al.| title=A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. | journal=JAMA Psychiatry | year= 2013 | volume= 70 | issue= 12 | pages= 1347-54 | pmid=24153411 | doi=10.1001/jamapsychiatry.2013.2216 | pmc=PMC4131728 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24153411  }} </ref>
===Monitoring===
* State-wide prescription monitoring programs is associated with a reduction of possible opioid diversion by 85%.<ref name="pmid24677496">{{cite journal| author=Surratt HL, O'Grady C, Kurtz SP, Stivers Y, Cicero TJ, Dart RC et al.| title=Reductions in prescription opioid diversion following recent legislative interventions in Florida. | journal=Pharmacoepidemiol Drug Saf | year= 2014 | volume= 23 | issue= 3 | pages= 314-20 | pmid=24677496 | doi=10.1002/pds.3553 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24677496  }} </ref> An ecological study in the state of Florida from that the rate of new investigations of possible diversion of oxycodone reported to the Drug Diversion program of the [http://www.radars.org/ Researched Abuse Diversion and Addiction-Related Surveillance System] dropped from 49.81/100,000 to 7.6/100,000 of the general population.<ref name="pmid24677496"/>


===Double effect===
===Double effect===
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With exceptions such as Shipman, UK doctors are very cautious about shortening life.<ref>Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9</ref> The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs.  Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.
With exceptions such as Shipman, UK doctors are very cautious about shortening life.<ref>Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9</ref> The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs.  Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.
===Tolerance===
''[[Drug tolerance|Tolerance]]'' is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others - tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects.
Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers<ref>Santillán R, Maestre JM, Hurlé MA, Flórez J. "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report." ''Pain''. 1994 Jul;58(1):129-32. PMID 7970835</ref><ref>Smith FL, Dombrowski DS, Dewey WL. "Involvement of intracellular calcium in morphine tolerance in mice." ''Pharmacology, Biochemistry, and Behavior''. 1999 Feb;62(2):381-8. PMID 9972707</ref>, [[intrathecal]] [[magnesium]]<ref>McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "[http://www.anesthesia-analgesia.org/cgi/reprint/86/4/830 Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats.]" ''Anesthesia and Analgesia''. 1998 Apr;86(4):830-6. PMID 9539610</ref> and [[zinc]]<ref>Larson AA, Kovács KJ, Spartz AK. "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance." ''European Journal of Pharmacology''. 2000 Nov 3;407(3):267-72. PMID 11068022</ref>, and [[NMDA antagonist]]s such as [[ketamine]].<ref>Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors." Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33. PMID 8851162</ref>
Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common<ref>http://www.worldwidehealthcenter.net/articles-360.html</ref> due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.
===Dependence===
''[[Drug dependence|Dependence]]'' is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed.  The withdrawal symptoms include severe [[dysphoria]], [[sweating]], [[nausea]], rhinorrea, depression, severe fatigue, [[vomiting]] and [[pain]].  Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.<ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref>  The speed and severity of withdrawal depends on the half-life of the opioid — [[heroin]] and [[morphine]] withdrawal occur more quickly and are more severe than [[methadone]] withdrawal, but methadone withdrawal takes longer.  The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can also be treated with other medications, but with a low efficacy.<ref>Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms.  Addict Biol. 2005 Jun;10(2):165-9. PMID: 16191669 </ref>  Dependence also occurs for most other drugs, including [[caffeine]] and [[alcohol]].  The DSM-IV Criteria for opioid withdrawal is (available from: http://www.ncbi.nlm.nih.gov/books/NBK64247/)
A. Either of the following:
* Cessation of or reduction in opioid use that has been heavy and for several weeks or longer
* Administration of an opioid antagonist after a period of opioid use
B. Three (or more) of the following (developing within minutes to several days after Criterion A):
* Diarrhea
* Dysphoric mood
* Fever
* Insomnia
* Lacrimation or rhinorrhea
* Muscle aches
* Nausea or vomiting
* Pupillary dilation, piloerection, or sweating
* Yawning
C. The symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
D. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.
===Addiction===
''[[Drug addiction|Addiction]]'' is the process whereby physical and/or psychological addiction develops to a drug - including opioids.  The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug.  Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.<ref>''Oxford Textbook of Palliative Medicine'', 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref>
===Abuse===
''[[Drug abuse]]'' is the misuse of drugs producing negative consequences.


==References==
==References==

Latest revision as of 15:34, 18 October 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Adverse Reactions

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.[1]

Oxycodone and codeine may increase mortality relative to codeine and hydrocodone[2] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[2] 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.[3]

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.[4]

Serious drug toxicity from long-term use may be low according to one systematic review.[5]

Common adverse reactions in patients taking opioids for pain relief:

These include: nausea and vomiting, drowsiness, dry mouth, miosis, and constipation. Fortunately, most of these are not a problem (see Treating Opioid Adverse Effects below).

Infrequent adverse reactions in patient taking opioids for pain relief:

These include: dose-related respiratory depression (see below), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil).

Gastroparesis

Opioid use may be associated with gastroparesis[6], possibly via stimulation of μ (MOP; β-endorphin) and maybe δ (DOP; enkephalin) receptors.

Codeine may be more likely to affect the gastrointestinal tract[7].

Buprenorphine, a partial agonist at the μ receptor, has also been reported to cause gastroparesis[8].

The affect of tramadol is not clear[9].

Treatment may include sympatholyic medications such as acute phentolamine or chronic clonidine[10].

Male hypogonadism

Chronic opioids may cause male hypogonadism.[11][12]

Employability

Use of opioids may be a risk factor for failing to return to work.[13][14]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.[15]

Impaired judgment

Opioids may increase risk of traffic accidents[16] and accidental falls[17].

Opioid Induced Hyperalgesia

Opioid-induced hyperalgesia is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly. [18] [19] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. [20] [21]

Sleep disorders

In a small study of patients on chronic opioids, about half had sleep disorders[22]:

Mortality and Overdose

Death from overdose on opioids may be more common than traffic accidents in the United States.[23] The rate of overdose is increasing faster among women and men according to the Centers for Disease Controll.[24]

Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.[25]

Overdose may be more common with with doses equivalent to more than 100 mg/day of morphine.[26] Overdose may[27] or may not[26] 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.[28]

Other adverse effects

Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

Treating opioid adverse effects

Most adverse effects can be managed successfully. (For more complete information see [29] and the online palliative care formulary available on Palliativedrugs.com.)

Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.

Vomiting: if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.

Constipation: this develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation ... is treated [with laxatives and stool-softeners]" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe” and “can be a very considerable complication” (Abse 1982, 129) if it is ignored.

Respiratory depression: Although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem.

Reversing the effect of opioids: Opioid effects can be rapidly reversed with an opioid antagonist such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose (e.g. naloxone 400 microg) but giving this in small doses (e.g. naloxone 40 microg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

How safe are opioids? A world view

There are a number of paradoxical beliefs about opioids:

  • 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms,[30] and yet a follow-up study showed that UK doctors are particularly cautious about shortening life.[31]
  • There is a belief that the use of opioids in pain is a fine balance between relief and hastening death, and yet palliative care physicians do not find themselves faced with the dilemma of relieving symptoms at the risk of shortening life.[32]
  • The Dutch public equate high dose morphine and sedation with euthanasia,[33] and yet it is the least used class of drug used for euthanasia in the Netherlands.

However, studies around the globe over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,[34] and that sedative dose increases were not associated with shortened survival (n=237).[35] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[36] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[37] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[38] The survival of Japanse patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.[39] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[40] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[41] Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.[42] Even when opioids are given intravenously, respiratory depression is not seen.[43]

Using opioids safely

  • Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg every four hours (or morphine by injection 1–2.5mg every four hours). Higher doses can be used if the patient was already on weaker analgesics.
  • Titration: this describes the adjustment of a drug dose to a patient, while allowing the patient’s body time to adjust to the drug to minimise adverse effects. Titration is done in 25–50% steps every 1–2 days.
  • Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range".
  • Dose range: this is very wide but usually lies between 30–500mg per 24 hours of oral morphine, but with a median of 90mg (or 15mg every four hours). It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.[44]
  • When discontinuing opioids in tolerant users, a taper of buprenorphine over 4 weeks may be used.[45]

Double effect

The principle of double effect is not used in palliative care. Doctors are not faced with the dilemma of giving a potentially lethal drug dose to a distressed patient.[46]

A palliative care doctor gives repeated, small doses of one or more drugs, each titrated to an individual until the symptoms are eased, while doing everything possible to avoid toxicity. Doctors who give 30–60 times the required dose of morphine or diamorphine, usually as a single intravenous dose, are acting either negligently or maliciously. Since drug records should exist for opioids, there is a clear audit trail to follow if a subsequent investigation is required.

With exceptions such as Shipman, UK doctors are very cautious about shortening life.[47] The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs. Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 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.
  3. ↑ 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. PMC 2935998. PMID 20590588.
  4. ↑ Martell BA, O'Connor PG, Kerns RD; 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.
  5. ↑ 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.
  6. ↑ Camilleri M, Lembo A, Katzka DA (2017). "Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits". Clin Gastroenterol Hepatol. 15 (9): 1338–1349. doi:10.1016/j.cgh.2017.05.014. PMC 5565678. PMID 28529168.
  7. ↑ Leppert W (2012). "The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities". Contemp Oncol (Pozn). 16 (2): 125–31. doi:10.5114/wo.2012.28792. PMC 3687404. PMID 23788866.
  8. ↑ Jakobovits SL, McDonough M, Chen RY (2007). "Buprenorphine-associated gastroparesis during in-patient heroin detoxification". Addiction. 102 (3): 490–1. doi:10.1111/j.1360-0443.2006.01684.x. PMID 17298658.
  9. ↑ Maurer AH, Krevsky B, Knight LC, Brown K (1996). "Opioid and opioid-like drug effects on whole-gut transit measured by scintigraphy". J Nucl Med. 37 (5): 818–22. PMID 8965152.
  10. ↑ Phillips WJ, Tollefson B, Johnson A, Abell T, Lerant A (2006). "Relief of acute pain in chronic idiopathic gastroparesis with intravenous phentolamine". Ann Pharmacother. 40 (11): 2032–6. doi:10.1345/aph.1H255. PMID 17003080.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Volinn E, Fargo JD, Fine PG (2009). "Opioid therapy for nonspecific low back pain and the outcome of chronic work loss". Pain. 142 (3): 194–201. doi:10.1016/j.pain.2008.12.017. PMID 19181448.
  15. ↑ 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.
  16. ↑ 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
  17. ↑ 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.
  18. ↑ Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." Am J Hosp Palliat Care. 2003 Nov-Dec;20(6):459-61. PMID 14649563
  19. ↑ Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." J Pain Palliat Care Pharmacother. 2007;21(1):15-25. PMID 17430825
  20. ↑ Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):291-4. Review. PMID 16082916
  21. ↑ Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." J Pain Palliat Care Pharmacother. 2004;18(3):75-9. Review. PMID 15364634
  22. ↑ Rose AR, Catcheside PG, McEvoy RD, Paul D, Kapur D, Peak E; et al. (2014). "Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy". J Clin Sleep Med. 10 (8): 847–52. doi:10.5664/jcsm.3950. PMC 4106937. PMID 25126029.
  23. ↑ Template:Err (Template:Err). "Drug deaths now outnumber traffic fatalities in U.S., Times analysis shows - latimes.com". Los Angeles Times. Los Angeles: Tribune Co. ISSN 0458-3035. Retrieved September 23, 2011. Check date values in: |date= (help)
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 26.0 26.1 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.
  27. ↑ 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.
  28. ↑ need to dig up the Cornell handbook
  29. ↑ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  30. ↑ Seale C. National survey of end-of-life decisions made by UK medical practitioners, Palliative Medicine 2006; 20(1): 3–10.
  31. ↑ Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9.
  32. ↑ George R, Regnard C. Lethal opioids or dangerous prescribers? Palliative Medicine, 2007; 21: 77-80.
  33. ↑ Rietjens JAC et al Preferences of the Dutch general public for a good death and associations with attitudes towards end-of-life decision-making. Palliative Medicine 2006; 20(7): 685–92.
  34. ↑ Regnard C and Badger C. Opioids, sleep and the time of death. Palliative Medicine, 1987; 1(2): 107–110.
  35. ↑ Sykes N. Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Int Med 2003: 163(3): 341–4.
  36. ↑ Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliative Medicine. 1997: 11(4): 277–81.
  37. ↑ Good PD, Ravenscroft PJ, Cavenagh J. Effects of opioids and sedatives on survival in an Australian inpatient palliative care population. Int Med J. 2005: 35(9): 512–7.
  38. ↑ Hu WY, Chiu TY, Cheng SY, Chen CY. Morphine for dyspnoea control in terminal cancer patients: is it appropriate in Taiwan? J Pain & Symp Manag. 2004: 28(4): 356–63.
  39. ↑ Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain & Symp Manag. 2001: 21(4): 282–9.
  40. ↑ Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? Chest. 2004: 126(1): 286–93.
  41. ↑ Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnoea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind control trial. Annals of Oncology. 1999: 10(12): 1511–4.
  42. ↑ Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnoea of terminal cancer patients. J Pain & Symp Manag, 1990: 5(6): 341–44.
  43. ↑ Bassam E, et al Respiratory function during parenteral opioid titration for cancer pain. Palliative Medicine, 2007; 21: 81-86.
  44. ↑ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  45. ↑ Sigmon SC, Dunn KE, Saulsgiver K, Patrick ME, Badger GJ, Heil SH; et al. (2013). "A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers". JAMA Psychiatry. 70 (12): 1347–54. doi:10.1001/jamapsychiatry.2013.2216. PMC 4131728. PMID 24153411.
  46. ↑ George R, Regnard C. Lethal opioids or dangerous prescribers? Palliative Medicine, 2007; 21: 77-80.
  47. ↑ Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9


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