Editing Morphine (section)

=== Reinforcement disorders ===

==== Addiction ====

[[File:Santiago Rusinol Before the Morphine.jpg|thumb|left|''Before the Morphine'' by [[Santiago Rusiñol]]]]

Morphine is a highly [[addictive]] substance. Multiple studies, including one by ''The Lancet'', ranked morphine/heroin as the #1 most addictive substance, followed by [[cocaine]] at #2, [[nicotine]] #3, [[barbiturates]] at #4, and [[ethanol]] at #5. In controlled studies comparing the physiological and subjective effects of [[heroin]] and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with heroin crossing the [[blood–brain barrier]] slightly quicker. No difference in subjects' self-rated feelings of [[euphoria]], ambition, nervousness, relaxation, or drowsiness.<ref name="martin and fraser" /> Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids [[hydromorphone]], [[fentanyl]], [[oxycodone]], and [[pethidine]], former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin also produced higher rates of euphoria and other positive subjective effects when compared to these other opioids.<ref name="martin and fraser" /> The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin is an ester of morphine and morphine [[prodrug]], essentially meaning they are identical drugs ''in vivo''. Heroin is converted to morphine before binding to the [[opioid receptor]]s in the brain and spinal cord, where morphine causes subjective effects, which is what the addicted individuals are seeking.<ref name="NIDA-2013">{{cite web |url = http://www.nida.nih.gov/infofacts/heroin.html |title = Heroin |author = National Institute on Drug Abuse (NIDA) |date = April 2013 |website = DrugFacts |publisher = U.S. National Institutes of Health |url-status = dead |archive-url = https://web.archive.org/web/20051130022758/http://www.nida.nih.gov/Infofacts/heroin.html |archive-date = 30 November 2005 |access-date = 29 April 2008 }}</ref>

==== Tolerance ====
Several hypotheses are given about how tolerance develops, including opioid receptor [[phosphorylation]] (which would change the receptor conformation), functional decoupling of receptors from [[G-proteins]] (leading to receptor desensitization),<ref>{{cite journal | vauthors = Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR | title = Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone | journal = Epilepsy Research | volume = 83 | issue = 2–3 | pages = 261–4 | date = February 2009 | pmid = 19059761 | doi = 10.1016/j.eplepsyres.2008.10.011 | s2cid = 21651602 }}</ref> μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the [[cyclic adenosine monophosphate|cAMP]] pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt<ref>{{cite journal | vauthors = Koch T, Höllt V | title = Role of receptor internalization in opioid tolerance and dependence | journal = Pharmacology & Therapeutics | volume = 117 | issue = 2 | pages = 199–206 | date = February 2008 | pmid = 18076994 | doi = 10.1016/j.pharmthera.2007.10.003 }}</ref>).

==== Dependence and withdrawal ====
{{See also|Opioid use disorder|Opioid withdrawal}}
{{more citations needed|section|date=November 2019}}
Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that of [[barbiturates]], [[benzodiazepines]], [[alcohol (drug)|alcohol]], or [[sedative]]-hypnotics, is not fatal by itself in otherwise healthy people.

Acute morphine withdrawal, along with that of any other opioid, proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited{{by whom|date=November 2010}}, they are:
* '''Stage I''', 6&nbsp;h to 14&nbsp;h after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate [[dysphoria]]
* '''Stage II''', 14&nbsp;h to 18&nbsp;h after last dose: [[Yawn]]ing, heavy [[perspiration]], mild [[Depression (mood)|depression]], [[lacrimation]], [[crying]], headaches, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state)
* '''Stage III''', 16&nbsp;h to 24&nbsp;h after last dose: Increase in all of the above, [[Mydriasis|dilated pupils]], [[Goose bumps|piloerection]] (goose bumps),<ref>{{cite web |url = http://www.merriam-webster.com/words-at-play/why-do-we-quit-cold-turkey |title = Why do We Quit 'Cold Turkey'? |access-date = 21 November 2016 |url-status = live |archive-url = https://web.archive.org/web/20161121175014/http://www.merriam-webster.com/words-at-play/why-do-we-quit-cold-turkey |archive-date = 21 November 2016 }}</ref> muscle twitches, [[hot flash]]es, cold flashes, aching bones and muscles, [[Anorexia (symptom)|loss of appetite]], and the beginning of intestinal cramping
* '''Stage IV''', 24&nbsp;h to 36&nbsp;h after last dose: Increase in all of the above including severe cramping, [[restless leg syndrome|restless legs syndrome]] (RLS), loose stool, [[insomnia]], elevation of blood pressure, [[fever]], increase in frequency of breathing and tidal volume, [[tachycardia]] (elevated pulse), [[Psychomotor agitation|restlessness]], nausea
* '''Stage V''', 36&nbsp;h to 72&nbsp;h after last dose: Increase in all of the above, fetal position, vomiting, free and frequent liquid diarrhea, weight loss of 2&nbsp;kg to 5&nbsp;kg per 24&nbsp;h, increased [[White blood cell|white cell count]], and other blood changes
* '''Stage VI''', after completion of above: Recovery of appetite and normal bowel function, beginning of transition to [[Post-acute-withdrawal syndrome|post-acute withdrawal symptoms]] that are mainly psychological, but may also include increased sensitivity to pain, [[hypertension]], [[colitis]] or other gastrointestinal afflictions related to motility, and problems with weight control in either direction

In advanced stages of withdrawal, ultrasonographic evidence of pancreatitis has been demonstrated in some patients and is presumably attributed to spasm of the pancreatic [[sphincter of Oddi]].<ref>{{cite web |url = http://www.livestrong.com/article/68215-opiate-withdrawal-stages/ |title = Opiate Withdrawal Stages |access-date = 13 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140605063405/http://www.livestrong.com/article/68215-opiate-withdrawal-stages/ |archive-date = 5 June 2014 }}</ref>

The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually 6&nbsp;h to 12&nbsp;h) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, [[dysphoria]], sweating, and, in some cases, a strong drug craving. Severe headache, restlessness, [[irritability]], loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases,<ref name="Chan, Irvine, and White">{{cite journal | vauthors = Chan R, Irvine R, White J | title = Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat | journal = European Journal of Pharmacology | volume = 368 | issue = 1 | pages = 25–33 | date = February 1999 | pmid = 10096766 | doi = 10.1016/S0014-2999(98)00984-4 }}</ref> which have potential to cause a heart attack, blood clot, or stroke.

Chills or cold flashes with goose bumps alternating with flushing (hot flashes), kicking movements of the legs,<ref name="NIDA-2013" /> and excessive sweating are also characteristic symptoms.<ref>{{cite web |url = http://www.nhtsa.dot.gov/People/injury/research/job185drugs/morphine.htm |title = Morphine (and Heroin) |website = Drugs and Human Performance Fact Sheets |publisher = U.S. National Traffic Safety Administration |url-status = dead |archive-url = https://web.archive.org/web/20061003085645/http://www.nhtsa.dot.gov/people/injury/research/job185drugs/morphine.htm |archive-date = 3 October 2006 |access-date = 17 May 2007 }}</ref> Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48&nbsp;h and 96&nbsp;h after the last dose and subside after about 8 to 12 days. Sudden discontinuation of morphine by heavily [[Drug dependence|dependent]] users who are in poor health is rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.<ref>{{cite web |url = http://www.justice.gov/dea/concern/narcotics.html |title = Narcotics |website = DEA Briefs & Background, Drugs and Drug Abuse, Drug Descriptions |publisher = U.S. Drug Enforcement Administration |url-status = unfit |archive-url = https://web.archive.org/web/20120114150200/http://www.justice.gov/dea/concern/narcotics.html |archive-date = 14 January 2012 }}</ref><ref>{{cite book | vauthors = Dalrymple T |author-link = Theodore Dalrymple |title = Romancing Opiates: Pharmacological Lies and the Addiction Bureaucracy |publisher = Encounter |year = 2006 |pages = [https://archive.org/details/romancingopiates00theo/page/160 160] |url = https://archive.org/details/romancingopiates00theo/page/160 |isbn = 978-1-59403-087-1 }}</ref>

The psychological dependence associated with morphine [[Substance use disorder|addiction]] is complex and protracted. Long after the physical need for morphine has passed, addicts will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is usually a long and painful process. Addicts often experience severe depression, anxiety, insomnia, mood swings, forgetfulness, low [[self-esteem]], [[confusion]], [[paranoia]], and other psychological problems. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days including psychological dependence. A high probability of relapse exists after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony of morphine's addictive and reinforcing nature is its relapse rate. Users of morphine have one of the highest relapse rates among all drug users, ranging up to 98% in the estimation of some medical experts.<ref>{{cite book | vauthors = O'Neil MJ |title = The Merck index: an encyclopedia of chemicals, drugs, and biological |year = 2006 |publisher = Merck |location = Whitehouse Station, N.J. |isbn = 978-0-911910-00-1 }}</ref>