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Physical dependence is a physical condition caused by chronic use of a
tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. 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 Post-acute withdrawal syndrome (PAWS) is a hypothesized set of persistent impairments that occur after withdrawal from alcohol, opiates, benzodiazepines, antidepressants, and other substances. Infants born to mothers who used substances of depend ...
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. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.


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. 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. 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. 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 Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
, 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) * All GABA agonists and positive allosteric modulators of both the GABA-A ionotropic receptor and
GABA-B GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolariz ...
metabotropic receptor subunits, including (partial list): ** alcohol ( alcoholic beverage) (cf. alcohol dependence, alcohol withdrawal, delirium tremens) ** 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 Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
) such as
zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases th ...
and zolpidem. ** gamma-hydroxybutyric acid (GHB) and 1,4-butanediol ** carisoprodol (Soma) and related
carbamates In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formall ...
(
tybamate Tybamate (INN; Solacen, Tybatran, Effisax) is an anxiolytic of the carbamate family. It is a prodrug for meprobamate in the same way as the better known drug carisoprodol. It has liver enzyme inducing effects similar to those of phenobarbital but ...
and meprobamate) ** baclofen (Lioresal) and its non-chlorinated analogue phenibut ** chloral hydrate ** glutethimide ** clomethiazole ** methaqualone (Quaalude) * nicotine ( tobacco) (cf. nicotine withdrawal) * gabapentinoids such as gabapentin (Neurontin), pregabalin (Lyrica), and phenibut (Noofen), which are inhibitors of α2δ subunit-containing *
antiepileptic Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
drugs such as valproate, lamotrigine,
tiagabine Tiagabine (trade name Gabitril) is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder. Medical uses Tiagabine is ...
,
vigabatrin Vigabatrin, brand name Sabril, is a medication used to treat epilepsy. It became available as a generic medication in 2019. It works by inhibiting the breakdown of γ-aminobutyric acid (GABA). It is also known as γ-vinyl-GABA, and is a stru ...
, carbamazepine and oxcarbazepine, and
topiramate Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence. For epilepsy this includes treatment for genera ...
* antipsychotic drugs such as clozapine, risperidone, olanzapine, haloperidol, thioridazine, etc. * commonly prescribed antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (cf. SSRI/SNRI withdrawal syndrome) * blood pressure medications, including beta blockers such as
propanolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance an ...
and
alpha-adrenergic agonist The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
s such as clonidine *
androgenic-anabolic steroids Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects t ...
* glucocorticoids


Rebound syndrome

A wide range of drugs whilst not causing a true physical dependence can still cause withdrawal symptoms or
rebound effects The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
during dosage reduction or especially abrupt or rapid withdrawal. These can include caffeine, stimulants, steroidal drugs and antiparkinsonian drugs. It is debated whether the entire antipsychotic drug class causes true physical dependency, a subset, or if none do. But, if discontinued too rapidly, it could cause an acute withdrawal syndrome. 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 The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
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. 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).


See also

* Drug tolerance * Psychological dependence *
Rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
* Substance dependence


References


External links


National Institutes of Health MedlinePlus Encyclopedia
{{Psychoactive substance use Substance dependence Substance-related disorders