Physical dependence

Short description: Physical condition caused by chronic use of a tolerance-forming drug

Addiction and dependence glossary[1][2][3][4]

* addiction – a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences
* addictive behavior – a behavior that is both rewarding and reinforcing
* addictive drug – a drug that is both rewarding and reinforcing
* dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
* drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
* drug withdrawal – symptoms that occur upon cessation of repeated drug use
* physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
* psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
* reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
* rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
* sensitization – an amplified response to a stimulus resulting from repeated exposure to it
* substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
* tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

v * d * e

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms.[5][6] Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines.[7] To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.[8]

## Contents

* 1 Symptoms
* 2 Treatment
* 3 Drugs that cause physical dependence
* 4 Rebound syndrome
* 5 See also
* 6 References
* 7 External links

## Symptoms

Physical dependence can manifest itself in the appearance of both physical and psychological symptoms which are caused by physiological adaptions in the central nervous system and the brain due to chronic exposure to a substance. Symptoms which may be experienced during withdrawal or reduction in dosage include increased heart rate and/or blood pressure, sweating, and tremors.[9] More serious withdrawal symptoms such as confusion, seizures, and visual hallucinations indicate a serious emergency and the need for immediate medical care. Sedative hypnotic drugs such as alcohol, benzodiazepines, and barbiturates are the only commonly available substances that can be fatal in withdrawal due to their propensity to induce withdrawal convulsions. Abrupt withdrawal from other drugs, such as opioids can cause an extremely painful withdrawal that is very rarely fatal in patients of general good health and with medical treatment, but is more often fatal in patients with weakened cardiovascular systems; toxicity is generally caused by the often-extreme increases in heart rate and blood pressure (which can be treated with clonidine), or due to arrhythmia due to electrolyte imbalance caused by the inability to eat, and constant diarrhea and vomiting (which can be treated with loperamide and ondansetron respectively) associated with acute opioid withdrawal, especially in longer-acting substances where the diarrhea and emesis can continue unabated for weeks, although life-threatening complications are extremely rare, and nearly non-existent with proper medical management.

## Treatment

Treatment for physical dependence depends upon the drug being withdrawn and often includes administration of another drug, especially for substances that can be dangerous when abruptly discontinued or when previous attempts have failed.[10] Physical dependence is usually managed by a slow dose reduction over a period of weeks, months or sometimes longer depending on the drug, dose and the individual.[7] A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.

## Drugs that cause physical dependence

* All µ-opioids with any (even slight) agonist effect, such as (partial list) morphine, heroin, codeine, oxycodone, buprenorphine, nalbuphine, methadone, and fentanyl, but not agonists specific to non-µ opioid receptors, such as salvinorin A (a k-opioid agonist), nor opioid antagonists or inverse agonists, such as naltrexone (a universal opioid inverse agonist)[11]
* All GABA agonists and positive allosteric modulators of both the GABA-A ionotropic receptor and GABA-B metabotropic receptor subunits, including (partial list):
* alcohol (alcoholic beverage) (cf. alcohol dependence, alcohol withdrawal, delirium tremens)[12]
* barbiturates such as phenobarbital, sodium thiopental and secobarbital
* benzodiazepines such as diazepam (Valium), lorazepam (Ativan), and alprazolam (Xanax) (see benzodiazepine dependence and benzodiazepine withdrawal syndrome)
* nonbenzodiazepine hypnotics (z-drugs) such as zopiclone and zolpidem.[13]
* gamma-hydroxybutyric acid (GHB) and 1,4-butanediol[14]
* carisoprodol (Soma) and related carbamates (tybamate and meprobamate)
* baclofen (Lioresal) and its non-chlorinated analogue phenibut[citation needed]
* chloral hydrate
* glutethimide
* clomethiazole
* methaqualone (Quaalude)
* nicotine (tobacco) (cf. nicotine withdrawal)[15][16]
* gabapentinoids such as gabapentin (Neurontin), pregabalin (Lyrica), and phenibut (Noofen), which are inhibitors of α2δ subunit-containing VDCCs[17][18]
* antiepileptic drugs such as valproate, lamotrigine, tiagabine, vigabatrin, carbamazepine and oxcarbazepine, and topiramate[17][19][20]
* antipsychotic drugs such as clozapine, risperidone, olanzapine, haloperidol, thioridazine, etc.[21]
* commonly prescribed antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (cf. SSRI/SNRI withdrawal syndrome)[22][23][24]
* blood pressure medications, including beta blockers such as propanolol and alpha-adrenergic agonists such as clonidine[25][26]
* androgenic-anabolic steroids[27][28]
* glucocorticoids[29]

## Rebound syndrome

Main article: Medicine:Rebound effect

A wide range of drugs whilst not causing a true physical dependence can still cause withdrawal symptoms or rebound effects during dosage reduction or especially abrupt or rapid withdrawal.[30][31] These can include caffeine,[32] stimulants,[33][34][35][36] steroidal drugs and antiparkinsonian drugs.[37] It is debated whether the entire antipsychotic drug class causes true physical dependency, a subset, or if none do.[38] But, if discontinued too rapidly, it could cause an acute withdrawal syndrome.[39] When talking about illicit drugs rebound withdrawal, especially with stimulants, it is sometimes referred to as "coming down" or "crashing".

Some drugs, like anticonvulsants and antidepressants, describe the drug category and not the mechanism. The individual agents and drug classes in the anticonvulsant drug category act at many different receptors and it is not possible to generalize their potential for physical dependence or incidence or severity of rebound syndrome as a group so they must be looked at individually. Anticonvulsants as a group however are known to cause tolerance to the anti-seizure effect.[40] SSRI drugs, which have an important use as antidepressants, engender a discontinuation syndrome that manifests with physical side effects; e.g., there have been case reports of a discontinuation syndrome with venlafaxine (Effexor).[24]

## See also

* Drug tolerance
* Psychological dependence
* Rebound insomnia
* Substance dependence

## References

1. ↑ "Chapter 15: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 364–375. ISBN 9780071481274.
2. ↑ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience 15 (4): 431–443. PMID 24459410. "Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.".
3. ↑ "Glossary of Terms". Department of Neuroscience. http://neuroscience.mssm.edu/nestler/glossary.html. Retrieved 9 February 2015.
4. ↑ "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine 374 (4): 363–371. January 2016. doi:10.1056/NEJMra1511480. PMID 26816013. "Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.".
5. ↑ "Definition of physical dependence - NCI Dictionary of Cancer Terms". 2011-02-02. http://www.cancer.gov/dictionary?cdrid=454765.
6. ↑ "All about Addiction". Medical News Today. http://www.medicalnewstoday.com/info/addiction/.
7. ↑ 7.0 7.1 "Benzodiazepine dependence and withdrawal: identification and medical management". J Am Board Fam Pract 5 (2): 167–75. 1992. PMID 1575069.
8. ↑ "Withdrawal From Antidepressants: Symptoms, Causes, Treatments" (in en-US). http://www.webmd.com/depression/guide/withdrawal-from-antidepressants. "These symptoms are not technically the same thing as physical "withdrawal" from a drug.... Unlike drug withdrawal, antidepressant discontinuation effects are not related to addiction but can reflect physiological consequences of stopping a drug, just as when someone with diabetes stops insulin."
9. ↑ "Drug addiction (substance use disorder)". Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/drug-addiction/symptoms-causes/syc-20365112.
10. ↑ Jain, Raka; Majumder, Pradipta; Gupta, Tina (January 2013). "Pharmacological Intervention of Nicotine Dependence". BioMed Research International 2013: 278392. doi:10.1155/2013/278392. ISSN 2314-6133. PMID 24490153.
11. ↑ "The role of spinal neuropeptides and prostaglandins in opioid physical dependence". Br. J. Pharmacol. 136 (1): 37–48. May 2002. doi:10.1038/sj.bjp.0704681. PMID 11976266.
12. ↑ "Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3". Genes, Brain and Behavior 7 (5): 560–7. July 2008. doi:10.1111/j.1601-183X.2008.00391.x. PMID 18363856.
13. ↑ Sikdar S; Ayonrinde, O.; Sampson, E. (July 1998). "Physical dependence on zopiclone. Prescribing this drug to addicts may give rise to iatrogenic drug misuse". BMJ 317 (7151): 146. doi:10.1136/bmj.317.7151.146. PMID 9657802.
14. ↑ "Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence". Addiction 92 (1): 89–96. January 1997. doi:10.1111/j.1360-0443.1997.tb03640.x. PMID 9060200.
15. ↑ Kawazoe, Shingo; Shinkai, Takahiro (September 2015). "[Nicotine dependence]". Nihon Rinsho. Japanese Journal of Clinical Medicine 73 (9): 1516–1521. ISSN 0047-1852. PMID 26394514.
16. ↑ Baker, Timothy B.; Piper, Megan E.; Schlam, Tanya R.; Cook, Jessica W.; Smith, Stevens S.; Loh, Wei-Yin; Bolt, Daniel (November 2012). "Are Tobacco Dependence and Withdrawal Related Amongst Heavy Smokers? Relevance to Conceptualizations of Dependence". Journal of Abnormal Psychology 121 (4): 909–921. doi:10.1037/a0027889. ISSN 0021-843X. PMID 22642839.
17. ↑ 17.0 17.1 Tran KT; Hranicky D; Lark T; Jacob Nj (June 2005). "Gabapentin withdrawal syndrome in the presence of a taper". Bipolar Disord 7 (3): 302–4. doi:10.1111/j.1399-5618.2005.00200.x. PMID 15898970.
18. ↑ Weingarten (2019). "Acute phenibut withdrawal: A comprehensive literature review and illustrative case report". Bosnian Journal of Basic Medical Sciences (Department of Anesthesiology and Perioperative Medicine, Mayo Clinic) 19 (2): 125–129. PMID 30501608.
19. ↑ "Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep". Neurology 57 (9): 1650–4. November 2001. doi:10.1212/WNL.57.9.1650. PMID 11706106.
20. ↑ "Effects of the calcium antagonists verapamil and nitrendipine on carbamazepine withdrawal". Methods Find Exp Clin Pharmacol 21 (10): 669–71. December 1999. doi:10.1358/mf.1999.21.10.795757. PMID 10702963. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=6&p_RefId=795757.
21. ↑ Meyer, Jonathan M. (January 2011). "Pharmacotherapy of Psychosis and Mania" (in en). Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition (12 ed.). McGraw-Hill Education / Medical. p. 435. ISBN 9780071624428.
22. ↑ "[Hypomania/mania induced by cessation of antidepressant drugs"] (in tr). Turk Psikiyatri Derg 19 (3): 329–33. 2008. PMID 18791886. http://www.turkpsikiyatri.com/ftr.aspx?id=643.
23. ↑ "The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study". J. Psychopharmacol. (Oxford) 22 (3): 330–2. May 2008. doi:10.1177/0269881107087488. PMID 18515448.
24. ↑ 24.0 24.1 "Venlafaxine dependence in a patient with a history of alcohol and amineptine misuse". Addiction 103 (9): 1572–4. September 2008. doi:10.1111/j.1360-0443.2008.02266.x. PMID 18636997.
25. ↑ "MedlinePlus Medical Encyclopedia: Drug abuse and dependence". https://www.nlm.nih.gov/medlineplus/ency/article/001522.htm.
26. ↑ "Withdrawal syndrome following cessation of antihypertensive drug therapy". Int. J. Clin. Pract. 59 (5): 562–70. May 2005. doi:10.1111/j.1368-5031.2005.00520.x. PMID 15857353.
27. ↑ "Behavioural manifestations of anabolic steroid use". CNS Drugs 19 (7): 571–95. 2005. doi:10.2165/00023210-200519070-00002. PMID 15984895.
28. ↑ "Effects of androgenic-anabolic steroids in athletes". Sports Med 34 (8): 513–54. 2004. doi:10.2165/00007256-200434080-00003. PMID 15248788.
29. ↑ [1]
30. ↑ "Exacerbation of psychosis after discontinuation of carbamazepine treatment". Am J Psychiatry 145 (7): 878–9. July 1988. doi:10.1176/ajp.145.7.878. PMID 2898213.
31. ↑ "Antidepressant Withdrawal and Rebound Phenomena". Deutsches Ärzteblatt Online 116 (20): 355–361. May 2019. doi:10.3238/arztebl.2019.0355. PMID 31288917.
32. ↑ "Low-dose caffeine physical dependence in humans". J. Pharmacol. Exp. Ther. 255 (3): 1123–32. December 1990. PMID 2262896. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2262896.
33. ↑ "CNS stimulants and the look-alike drugs". Psychiatr. Clin. North Am. 7 (4): 689–701. December 1984. doi:10.1016/S0193-953X(18)30723-8. PMID 6151645.
34. ↑ "Can stimulant rebound mimic pediatric bipolar disorder?". J Child Adolesc Psychopharmacol 12 (1): 63–7. 2002. doi:10.1089/10445460252943588. PMID 12014597.
35. ↑ Danke F (1975). "[Methylphenidate addiction--Reversal of effect on withdrawal]" (in de). Psychiatr Clin (Basel) 8 (4): 201–11. PMID 1208893.
36. ↑ "A boy who stops taking stimulants for "ADHD": commentaries on a Pediatrics case study". Ethical Hum Sci Serv 4 (3): 189–209. 2002. PMID 15278983.
37. ↑ "[Risk related to withdrawal from non-psychotropic drugs]" (in fr). Thérapie 48 (5): 415–9. 1993. PMID 8146817.
38. ↑ Tierney, Lawrence M.; McPhee, Stephen J.; Papadakis, Maxine A. (2008). Current medical diagnosis & treatment, 2008. McGraw-Hill Medical. p. 916. ISBN 978-0-07-149430-4. https://archive.org/details/isbn_9780071494304.
39. ↑ BNF; British Medical Journal (2008). "Antipsychotic drugs". UK: British National Formulary. http://www.bnf.org/bnf/bnf/56/3209.htm.
40. ↑ Wolfgang Löscher; Dieter Schmidt (August 2006). "Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs". Epilepsia 47 (8): 1253–1284. doi:10.1111/j.1528-1167.2006.00607.x. PMID 16922870.

## External links

* National Institutes of Health MedlinePlus Encyclopedia

* v
* t
* e

Psychoactive substance-related disorder (F10–F19, 291–292; 303–305)

General|

* SID
* Substance intoxication / Drug overdose
* Substance-induced psychosis
* Withdrawal:
* Craving
* Neonatal withdrawal
* Post-acute-withdrawal syndrome (PAWS)
* SUD
* Substance abuse / Substance-related disorders
* Physical dependence / Psychological dependence / Substance dependence

Combined
substance use|

* SUD
* Polysubstance dependence
* SID
* Combined drug intoxication (CDI)

Alcohol|

| SID|

| Cardiovascular diseases|

* Alcoholic cardiomyopathy
* Alcohol flush reaction

|

Gastrointestinal diseases|

* Alcoholic liver disease (ALD):
* Alcoholic hepatitis
* Auto-brewery syndrome

Endocrine diseases|

* Alcoholic ketoacidosis (AKA)

Nervous
system diseases|

* Alcohol-related dementia (ARD)
* Alcohol intoxication
* Hangover

Neurological
disorders|

* Alcoholic hallucinosis
* Alcoholic polyneuropathy
* Alcohol-related brain damage
* Alcohol withdrawal syndrome:
* Alcoholic hallucinosis
* Delirium tremens (DTs)
* Fetal alcohol spectrum disorder (FASD)
* Fetal alcohol syndrome (FAS)
* Korsakoff syndrome
* Korsakoff psychosis
* Positional alcohol nystagmus (PAN)
* Wernicke–Korsakoff syndrome (WKS)
* Wernicke encephalopathy (WE)

Respiratory tract diseases|

* Alcohol-induced respiratory reactions
* Alcoholic lung disease

SUD|

* Alcoholism (alcohol use disorder (AUD))
* Binge drinking

Caffeine|

* SID
* Caffeine-induced anxiety disorder
* Caffeine-induced sleep disorder
* Caffeinism
* SUD
* Caffeine dependence

Cannabis|

* SID
* Cannabinoid hyperemesis syndrome (CHS)
* SUD
* Amotivational syndrome
* Cannabis use disorder (CUD)
* Synthetic cannabinoid use disorder

Cocaine|

* SID
* Cocaine intoxication
* Prenatal cocaine exposure (PCE)
* SUD
* Cocaine dependence

Hallucinogen|

* SID
* Acute intoxication from hallucinogens (bad trip)
* Hallucinogen persisting perception disorder (HPPD)

Nicotine|

* SID
* Nicotine poisoning
* Nicotine withdrawal
* SUD
* Nicotine dependence

Opioids|

* SID
* Opioid overdose
* SUD
* Opioid use disorder (OUD)

Sedative /
hypnotic|

* SID
* Kindling (sedative–hypnotic withdrawal)
* benzodiazepine: SID
* Benzodiazepine overdose
* Benzodiazepine withdrawal
* SUD
* Benzodiazepine use disorder (BUD)
* Benzodiazepine dependence
* barbiturate: SID
* Barbiturate overdose
* SUD
* Barbiturate dependence

Stimulants|

* SID
* Stimulant psychosis
* amphetamine: SUD
* Amphetamine dependence

Volatile
solvent|

* SID
* Sudden sniffing death syndrome (SSDS)
* Toluene toxicity
* SUD
* Inhalant abuse

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