{{Short description|Physical condition caused by chronic use of a tolerance-forming drug}} {{addiction glossary}} '''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.<ref name="Definition of physical dependence - NCI Dictionary of Cancer Terms">{{cite web |url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/physical-dependence |title=Definition of physical dependence - NCI Dictionary of Cancer Terms |access-date=2015-02-18|date=2011-02-02 }}</ref><ref>{{cite news | title = All about Addiction | publisher = Medical News Today | url = http://www.medicalnewstoday.com/info/addiction/ | access-date = 2015-02-18 }}</ref> Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, 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 as well as opioids.<ref name="pmid1575069">{{cite journal |vauthors=Landry MJ, Smith DE, McDuff DR, Baughman OL |title=Benzodiazepine dependence and withdrawal: identification and medical management |journal=J Am Board Fam Pract |volume=5 |issue=2 |pages=167–75 |year=1992 |pmid=1575069 }}</ref> To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.<ref>{{Cite web|title = Withdrawal From Antidepressants: Symptoms, Causes, Treatments|url = http://www.webmd.com/depression/guide/withdrawal-from-antidepressants|website = WebMD|access-date = 2016-02-20|language = en-US|quote = 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.}}</ref>
==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.<ref>{{cite web|title=Drug addiction (substance use disorder)|publisher=Mayo Clinic|url=https://www.mayoclinic.org/diseases-conditions/drug-addiction/symptoms-causes/syc-20365112|access-date=4 October 2020}}</ref> 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.<ref>{{Cite journal|title = Pharmacological Intervention of Nicotine Dependence|journal = BioMed Research International|date = January 2013|issn = 2314-6133|pmc = 3891736|pmid = 24490153|volume = 2013|article-number = 278392|doi = 10.1155/2013/278392|first1 = Raka|last1 = Jain|first2 = Pradipta|last2 = Majumder|first3 = Tina|last3 = Gupta|doi-access = free}}</ref> 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.<ref name="pmid1575069" /> 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)<ref name="pmid11976266">{{cite journal |vauthors=Trang T, Sutak M, Quirion R, Jhamandas K |title=The role of spinal neuropeptides and prostaglandins in opioid physical dependence |journal=Br. J. Pharmacol. |volume=136 |issue=1 |pages=37–48 |date=May 2002 |pmid=11976266 |pmc=1762111 |doi=10.1038/sj.bjp.0704681}}</ref> * All{{citation needed|date=November 2017}} 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)<ref name="pmid18363856">{{cite journal |vauthors=Kozell L, Belknap JK, Hofstetter JR, Mayeda A, Buck KJ |title=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 |journal=Genes, Brain and Behavior |volume=7 |issue=5 |pages=560–7 |date=July 2008 |pmid=18363856 |doi=10.1111/j.1601-183X.2008.00391.x |doi-access=free }}</ref> ** 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.<ref name="pmid9657802">{{cite journal |author=Sikdar S |title=Physical dependence on zopiclone. Prescribing this drug to addicts may give rise to iatrogenic drug misuse |journal=BMJ |volume=317 |issue=7151 |page=146 |date=July 1998 |pmid=9657802 |pmc=1113504 |doi= 10.1136/bmj.317.7151.146|last2=Ayonrinde |first2=O. |last3=Sampson |first3=E.}}</ref> ** gamma-hydroxybutyric acid (GHB) and 1,4-butanediol<ref name="pmid9060200">{{cite journal |vauthors=Galloway GP, Frederick SL, Staggers FE, Gonzales M, Stalcup SA, Smith DE |title=Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence |journal=Addiction |volume=92 |issue=1 |pages=89–96 |date=January 1997 |pmid=9060200 |doi= 10.1111/j.1360-0443.1997.tb03640.x}}</ref> ** carisoprodol (Soma) and related carbamates (tybamate, meprobamate, ethinamate etc.) ** baclofen (Lioresal) and its non-chlorinated analogue phenibut<ref>{{Cite journal|last1=Alvis|first1=Bret D.|last2=Sobey|first2=Christopher M.|date=January 2017|title=Oral Baclofen Withdrawal Resulting in Progressive Weakness and Sedation Requiring Intensive Care Admission|journal=The Neurohospitalist|volume=7|issue=1|pages=39–40|doi=10.1177/1941874416637404|issn=1941-8744|pmc=5167087|pmid=28042369}}</ref> ** chloral hydrate ** glutethimide ** clomethiazole ** methaqualone (Quaalude) * nicotine (tobacco) (cf. nicotine withdrawal)<ref>{{Cite journal|title = [Nicotine dependence]|journal = Nihon Rinsho. Japanese Journal of Clinical Medicine|date = September 2015|issn = 0047-1852|pmid = 26394514|pages = 1516–1521|volume = 73|issue = 9|first1 = Shingo|last1 = Kawazoe|first2 = Takahiro|last2 = Shinkai}}</ref><ref>{{Cite journal|title = Are Tobacco Dependence and Withdrawal Related Amongst Heavy Smokers? Relevance to Conceptualizations of Dependence|journal = Journal of Abnormal Psychology|date = November 2012|issn = 0021-843X|pmc = 3560396|pmid = 22642839|pages = 909–921|volume = 121|issue = 4|doi = 10.1037/a0027889|first1 = Timothy B.|last1 = Baker|first2 = Megan E.|last2 = Piper|first3 = Tanya R.|last3 = Schlam|first4 = Jessica W.|last4 = Cook|first5 = Stevens S.|last5 = Smith|first6 = Wei-Yin|last6 = Loh |author6-link=Wei-Yin Loh |first7 = Daniel|last7 = Bolt}}</ref> * gabapentinoids such as gabapentin (Neurontin), pregabalin (Lyrica), and phenibut (Noofen), baclofen (Lioresal), which are inhibitors of α<sub>2</sub>δ subunit-containing {{abbrlink|VDCCs|voltage-dependent calcium channels}}<ref name="Tran KT, Hranicky D, Lark T, Jacob Nj 2005 302–4">{{cite journal |author1=Tran KT |author2=Hranicky D |author3=Lark T |author4=Jacob Nj |title=Gabapentin withdrawal syndrome in the presence of a taper |journal=Bipolar Disord |volume=7 |issue=3 |pages=302–4 |date=June 2005 |pmid=15898970 |doi=10.1111/j.1399-5618.2005.00200.x }}</ref><ref>{{cite journal |last1=Weingarten |title=Acute phenibut withdrawal: A comprehensive literature review and illustrative case report |journal=Bosnian Journal of Basic Medical Sciences |year=2019 |volume=19 |issue=2 |pages=125–129 |publisher=Department of Anesthesiology and Perioperative Medicine, Mayo Clinic |pmid=30501608 |pmc=6535394 |doi=10.17305/bjbms.2018.4008 }}</ref> * antiepileptic drugs such as valproate, lamotrigine, tiagabine, vigabatrin, carbamazepine and oxcarbazepine, and topiramate<ref name="Tran KT, Hranicky D, Lark T, Jacob Nj 2005 302–4"/><ref>{{cite journal |vauthors=Hennessy MJ, Tighe MG, Binnie CD, Nashef L |title=Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep |journal=Neurology |volume=57 |issue=9 |pages=1650–4 |date=November 2001 |pmid=11706106 |doi= 10.1212/WNL.57.9.1650|s2cid=22885837 }}</ref><ref>{{cite journal |vauthors=Lazarova M, Petkova B, Staneva-Stoycheva D |title=Effects of the calcium antagonists verapamil and nitrendipine on carbamazepine withdrawal |journal=Methods Find Exp Clin Pharmacol |volume=21 |issue=10 |pages=669–71 |date=December 1999 |pmid=10702963 |doi= 10.1358/mf.1999.21.10.795757|url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=6&p_RefId=795757|url-access=subscription }}</ref> * antipsychotic drugs such as clozapine, risperidone, olanzapine, haloperidol, thioridazine, etc.<ref>{{Cite book|edition = 12|title = Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition|publisher = McGraw-Hill Education / Medical|date = January 2011|isbn = 978-0-07-162442-8|language = en|page = 435|chapter = Pharmacotherapy of Psychosis and Mania|last = Meyer|first = Jonathan M.}}</ref> * commonly prescribed antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (cf. SSRI/SNRI withdrawal syndrome)<ref>{{cite journal |vauthors=Kora K, Kaplan P |title=[Hypomania/mania induced by cessation of antidepressant drugs] |language=tr |journal=Turk Psikiyatri Derg |volume=19 |issue=3 |pages=329–33 |year=2008 |pmid=18791886 |url=http://www.turkpsikiyatri.com/ftr.aspx?id=643}}</ref><ref>{{cite journal |vauthors=Tint A, Haddad PM, Anderson IM |title=The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study |journal=J. Psychopharmacol. (Oxford) |volume=22 |issue=3 |pages=330–2 |date=May 2008 |pmid=18515448 |doi=10.1177/0269881107087488 }}</ref><ref name="Quaglio G, Schifano F, Lugoboni F 2008 1572–4">{{cite journal |vauthors=Quaglio G, Schifano F, Lugoboni F |title=Venlafaxine dependence in a patient with a history of alcohol and amineptine misuse |journal=Addiction |volume=103 |issue=9 |pages=1572–4 |date=September 2008 |pmid=18636997 |doi=10.1111/j.1360-0443.2008.02266.x }}</ref> * blood pressure medications, including beta blockers such as propranolol and alpha-adrenergic agonists such as clonidine<ref name="urlMedlinePlus Medical Encyclopedia: Drug abuse and dependence">{{cite web |url=https://www.medlineplus.gov/ency/article/001522.htm |title=MedlinePlus Medical Encyclopedia: Drug abuse and dependence |access-date=2008-12-21}}</ref><ref>{{cite journal |vauthors=Karachalios GN, Charalabopoulos A, Papalimneou V, etal |title=Withdrawal syndrome following cessation of antihypertensive drug therapy |journal=Int. J. Clin. Pract. |volume=59 |issue=5 |pages=562–70 |date=May 2005 |pmid=15857353 |doi=10.1111/j.1368-5031.2005.00520.x |s2cid=31449302 |doi-access=free }}</ref> * androgenic-anabolic steroids<ref name="pmid15984895">{{cite journal |vauthors=Trenton AJ, Currier GW |title=Behavioural manifestations of anabolic steroid use |journal=CNS Drugs |volume=19 |issue=7 |pages=571–95 |year=2005 |pmid=15984895 |doi= 10.2165/00023210-200519070-00002|s2cid=32243658 }}</ref><ref name="pmid15248788">{{cite journal |vauthors=Hartgens F, Kuipers H |title=Effects of androgenic-anabolic steroids in athletes |journal=Sports Med |volume=34 |issue=8 |pages=513–54 |year=2004 |pmid=15248788 |doi= 10.2165/00007256-200434080-00003|s2cid=15234016 }}</ref> * glucocorticoids<ref>[http://www.cqld.ca/livre/en/en/20-doping.htm] {{webarchive|url=https://web.archive.org/web/20130519163949/http://www.cqld.ca/livre/en/en/20-doping.htm|date=May 19, 2013}}</ref> * topical decongestants such as xylometazoline and oxymetazoline<ref>{{Cite journal |last=Lakatos |first=Lili |last2=Koltai |first2=Borbála Gabriella |last3=Ferencz |first3=Veronika |last4=Demetrovics |first4=Zsolt |last5=Rácz |first5=József |date=2025-03-28 |title=Does nose spray addiction exist? A qualitative analysis of addiction components in rhinitis medicamentosa |url=https://akjournals.com/view/journals/2006/14/1/article-p548.xml |journal=Journal of Behavioral Addictions |volume=14 |issue=1 |pages=548–560 |doi=10.1556/2006.2024.00078 |issn=2062-5871 |pmc=11974400 |pmid=39932504}}</ref>
==Rebound syndrome== {{Main|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.<ref>{{cite journal |vauthors=Heh CW, Sramek J, Herrera J, Costa J |title=Exacerbation of psychosis after discontinuation of carbamazepine treatment |journal=Am J Psychiatry |volume=145 |issue=7 |pages=878–9 |date=July 1988 |pmid=2898213 |doi=10.1176/ajp.145.7.878 }}</ref><ref>{{cite journal | vauthors = Henssler J, Heinz A, Brandt L, Bschor T | title = Antidepressant Withdrawal and Rebound Phenomena | journal = Deutsches Ärzteblatt Online | date=May 2019 | volume = 116 | issue = 20 | pages = 355–361 | doi=10.3238/arztebl.2019.0355 | pmid = 31288917| pmc = 6637660 }}</ref> These can include caffeine,<ref name="pmid2262896">{{cite journal |vauthors=Griffiths RR, Evans SM, Heishman SJ, etal |title=Low-dose caffeine physical dependence in humans |journal=J. Pharmacol. Exp. Ther. |volume=255 |issue=3 |pages=1123–32 |date=December 1990 |pmid=2262896 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2262896 |archive-date=2022-11-29 |access-date=2008-12-22 |archive-url=https://web.archive.org/web/20221129023345/https://jpet.aspetjournals.org/content/255/3/1123.long |url-status=dead }}</ref> stimulants,<ref>{{cite journal |vauthors=Lake CR, Quirk RS |title=CNS stimulants and the look-alike drugs |journal=Psychiatr. Clin. North Am. |volume=7 |issue=4 |pages=689–701 |date=December 1984 |pmid=6151645 |doi= 10.1016/S0193-953X(18)30723-8}}</ref><ref>{{cite journal |vauthors=Sarampote CS, Efron LA, Robb AS, Pearl PL, Stein MA |title=Can stimulant rebound mimic pediatric bipolar disorder? |journal=J Child Adolesc Psychopharmacol |volume=12 |issue=1 |pages=63–7 |year=2002 |pmid=12014597 |doi=10.1089/10445460252943588}}</ref><ref>{{cite journal |author=Danke F |title=[Methylphenidate addiction--Reversal of effect on withdrawal] |language=de |journal=Psychiatr Clin (Basel) |volume=8 |issue=4 |pages=201–11 |year=1975 |pmid=1208893 }}</ref><ref>{{cite journal |vauthors=Cohen D, Leo J, Stanton T, etal |title=A boy who stops taking stimulants for "ADHD": commentaries on a Pediatrics case study |journal=Ethical Hum Sci Serv |volume=4 |issue=3 |pages=189–209 |year=2002 |pmid=15278983 }}</ref> steroidal drugs and antiparkinsonian drugs.<ref>{{cite journal |vauthors=Chichmanian RM, Gustovic P, Spreux A, Baldin B |title=[Risk related to withdrawal from non-psychotropic drugs] |language=fr |journal=Thérapie |volume=48 |issue=5 |pages=415–9 |year=1993 |pmid=8146817 }}</ref> It is debated whether the entire antipsychotic drug class causes true physical dependency, a subset, or if none do.<ref name="isbn0-07-149430-8">{{cite book |author1=Tierney, Lawrence M. |author2=McPhee, Stephen J. |author3=Papadakis, Maxine A. |title=Current medical diagnosis & treatment, 2008 |url=https://archive.org/details/isbn_9780071494304 |url-access=registration |publisher=McGraw-Hill Medical |year=2008 |page=[https://archive.org/details/isbn_9780071494304/page/916 916] |isbn=978-0-07-149430-4 }}</ref> But, if discontinued too rapidly, it could cause an acute withdrawal syndrome.<ref>{{cite web | url = http://www.bnf.org/bnf/bnf/56/3209.htm | title = Antipsychotic drugs | access-date = 22 December 2008 | author = BNF | author-link = British National Formulary |author2=British Medical Journal | year = 2008 | publisher = British National Formulary | location = UK}}</ref> 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.<ref>{{cite journal |author1=Wolfgang Löscher |author2=Dieter Schmidt |title=Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs|journal=Epilepsia|volume=47 |issue=8 |pages=1253–1284 |date=August 2006 | doi=10.1111/j.1528-1167.2006.00607.x |pmid=16922870|doi-access=free }}</ref> 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).<ref name="Quaglio G, Schifano F, Lugoboni F 2008 1572–4"/>
==See also== *Drug tolerance *Psychological dependence *Rebound insomnia *Substance dependence
== References == {{reflist|2}}
==External links== * [https://www.medlineplus.gov/ency/article/001522.htm#Definition National Institutes of Health MedlinePlus Encyclopedia]
{{Psychoactive substance use}}
Category:Causes of death Category:Substance dependence Category:Substance-related disorders