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.[4][5] 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.[6] To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.[7]
Quick Facts
Addiction and dependence glossary[1][2][3] |
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- addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
- addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
- 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 socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
- 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
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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.[8] 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 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.[9] 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.[6] A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.
- 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)[10]
- All[citation needed] GABA agonists and positive allosteric modulators of both the GABA-A ionotropic receptor and GABA-B metabotropic receptor subunits, including (partial list):
- nicotine (tobacco) (cf. nicotine withdrawal)[15][16]
- gabapentinoids such as gabapentin (Neurontin), pregabalin (Lyrica), and phenibut (Noofen), which are inhibitors of α2δ subunit-containing VDCCsTooltip voltage-dependent calcium channels[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]
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]
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. 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.
Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. 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.
Landry MJ, Smith DE, McDuff DR, Baughman OL (1992). "Benzodiazepine dependence and withdrawal: identification and medical management". J Am Board Fam Pract. 5 (2): 167–75. PMID 1575069. "Withdrawal From Antidepressants: Symptoms, Causes, Treatments". WebMD. Retrieved 2016-02-20. 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.
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