Prolonged use of opioid analgesics induces pharmacodynamic tolerance, physical and psychological addiction. Cessation or reduction of opioid administration thus leads to opioid withdrawal, a condition associated with agitation, anxiety and autonomic nervous system disorders.
OW occurs in two stages. Initially, psychiatric symptoms predominate and patients show agitation, anxiety, loss of appetite and insomnia [4]. An increased sympathetic tone adds to this condition, worsens overall weakness, irritability and restlessness. Additional symptoms may partially be ascribed to imbalances of parasympathetic and sympathetic autonomous functions, partially to central nervous system arousal. Mydriasis as well as mild tachycardia and hypertension are characteristic findings. Gastrointestinal symptoms include abdominal pain, nausea, vomiting and diarrhea. Although hypothermia is less commonly detected, patients tend to feel cold and shiver but sweat nevertheless. They may show tremor and suffer from myalgia and muscle cramps. Lacrimation and mucous membrane secretion may be augmented.
Opioid addiction and OW are generally not diagnosed in otherwise healthy patients. Addiction to other drugs is frequently observed and while the vast majority of OW patients smokes, lesser shares of patients regularly consumes alcohol, pharmaceuticals and illegal drugs. Of note, tobacco consumption may exacerbate OW symptoms and render patients less responsive to therapy. Moreover, OW treatment may be significantly complicated by additional withdrawal syndromes. Psychiatric disorders are also common. Anxiety and panic disorder, depression, personality disorder and stress are frequent comorbidities [5]. It is not yet completely understood why prevalence rates of mental disorders are up to three times higher in opioid addicted people than in the general population [6].
Patients suffering from chronic pain and/or using opioids for prolonged periods of time are known to be at higher risk of suicide [7]. It has been suggested that this also applies to patients undergoing OW, although so far no studies have been conducted to this end.
The patient's medical history is of utmost importance for diagnosis of OW. For instance, recent changes in long-term opioid therapies for chronic pain may trigger OW and patients may readily report this upon inquiry. However, addiction to non-prescribed and illegal opioid drugs may be concealed. Also, patients may not associate flu-like symptoms to drug addiction and withdrawal and need to be questioned in this regard.
The American Psychiatric Association has defined clear criteria for diagnosis of OW [8]. As has been mentioned above, cessation or reduction of high-dose, prolonged opioid therapy induces OW and is therefore mandatory for its diagnosis. Alternatively, effects of a continued opioid therapy may have been drastically decreased by administration of opioid antagonists like naloxone or naltroxene. There needs to be a temporal relation between these events and onset of symptoms characteristic for OW. At least three of the following symptoms should be observed:
OW symptoms are unspecific. Thus, a thorough clinical examination, laboratory analyses of blood and urine samples should be performed. With regard to blood samples, establishment complete hemogram and blood chemistry are recommended. Diagnosis of OW also requires ruling out addiction and withdrawal from other drugs, psychological disorders, intrinsic diseases of the autonomic nervous system and other conditions possibly indicated by the results of laboratory test.
OW is not a life-threatening condition, but symptoms may be significantly alleviated if patients are detoxified in a controlled manner. Hospitalization may be necessary if psychiatric disorders or other comorbidities indicate continuous monitoring or if the patient's social environment constitutes a strong risk factor for relapses. Otherwise, an outpatient therapy may be sufficient.
Methadone, a full μ opioid receptor agonist, and buprenorphine, partial agonist at μ receptors are most frequently applied for opioid detoxification [9]. Slow release forms of other opioids as well as alpha-2 agonists may also be administered. Opioid detoxification with other opioids is based on cross-tolerance, i.e., they are less harmful than the addictive drug but nevertheless satisfy the body's need for opioids. They need to be tapered off slowly. Centrally acting sympathomimetics like lofexidine and clonidine mediate an overall reduction of the sympathetic tone which is why OW patients benefit from these compounds. They are particularly helpful to reduce symptoms that may be ascribed to an increased sympathetic tone. Withdrawal may occur and resolve earlier in patients treated with alpha-2 agonists, but the overall success of therapy based opioid substitution or antisympathotonic drugs is presumably very similar [10]. Side effects may interfere with therapeutic compliance and should be registered accordingly.
Of note, rapid detoxification may be achieved with opioid receptor antagonists naloxone and naltroxene. They fully block μ opioid receptors and therefore provide little relieve from OW symptoms. Therapeutic compliance is very low, which is why this approach should only be considered - if at all - when continuous monitoring can be guaranteed. Nevertheless, the risk of relapse is considered high [9]. Some studies recommend use of opioid receptor antagonists in motivated patients [11].
It is strongly recommended to supplement pharmacological detoxification with psychotherapy and possibly participation in a support group [12]. With regards to the former, distinct approaches promise similar results and patients may benefit from behavioral counseling, structured counseling as well as from family therapy. All have been shown to significantly improve the overall success of OW treatment and to reduce relapse rates [13].
OW is a painful yet not life-threatening process. Severity largely depends on the specific addictive drug and on duration of opioid use. Appropriate treatment may significantly relieve OW symptoms, but the risk of relapses is high.
Both legal and illegal drugs pertaining to the class of opioids may cause addiction and OW upon cessation or reduction of drug application.
In this context, treatment of chronic pain poses a major challenge: Prolonged administration of opioids induces drug tolerance and leads to addiction, but dose reduction causes insufficient analgesia, particularly due to tolerance induction. According to retrospective studies, approximately one out of six patients receiving opioids for chronic pain develops opioid addiction [1]. Opioids generally used for therapy of OW may serve as an alternative treatment of chronic pain [2].
No other opioid causes addiction as fast as heroin. Because heroin is an illegal drug, the inability to procure supplies - and single doses will have to be increased to compensate for drug tolerance - may have the patient suffering from severe OW without consulting health care givers.
According to statistics, opioid abuse is more common among men than it is among women. This particularly applies to use of heroin, which has a male-to-female ratio of three to one. Differences are less pronounced when considering legal opioids prescribed for pain and cough therapy.
Chronic pain is the main reason for prolonged use of opioid analgesics. Its incidence increases with age and thus, opioid addiction and OW upon dose reduction is more frequently seen in the elderly. In contrast, heroin addiction is typically encountered in adolescents and young adults. Early exposure to other legal and illegal drugs often precedes heroin use.
Opioids act on μ, κ, δ and ε receptors that are located in the central nervous system and in the gastrointestinal tract. Their physiological agonists are endorphins and enkephalins. Here, opioids mediate different effects:
Additionally, opioids cause imbalances of the autonomic nervous system by decreasing the overall sympathetic tone.
Tolerance to opioids is mainly pharmacodynamic and is caused by down-regulation of μ receptors and a regulatory increase of the sympathetic tone. These long-term effects account for the fact that a sudden cessation of opioid therapy results in dysphoria and autonomic nervous system disorders. In case of opioid analgesics and antitussives, such symptoms of OW may manifest after ending year-long therapies. Heroin, in contrast, triggers a very strong sense of euphoria and thus immediately causes psychological addiction.
Morphine and heroin mediate their effects mainly by binding to μ receptors. Because activation of this receptor triggers euphoria, administration of these compounds is associated with a high risk of addiction. Reduction of doses therefore evokes symptoms of OW. Partial μ and κ receptor agonists like buprenorphine are less potent analgesics but also bear lower risks of addiction and subsequent OW [3].
When considering opioid treatment for a patient suffering from chronic pain or comparable conditions that require strong analgesics or antitussives, benefits and possible side effects should be assessed. Moreover, patients should be advised to strictly follow treatment recommendations, to not increase single doses, augment application frequency or prolong the overall duration of therapy.
Patients should know about the risk of addiction and withdrawal. If treated for OW, they should be able to recognize early symptoms of relapses.
Opioids should be stored safe from unauthorized access. This applies to hospitals and medical practices as well as patients' homes.
Papaver somniferum, colloquially called opium poppy, is a Mediterranean plant whose sap contains pharmacologically active compounds such as morphine and codeine. Both are opiates, i.e., natural compounds. In contrast, semi-synthetic and synthetic drugs like heroin, hydromorphone, hydrocodone as well as fentanyl and methadone, respectively, are rather referred to as opioids. In this article, the term opioid will be used to refer to both classes of drugs.
Opioids are generally prescribed to treat moderate to severe pain and cough. They mainly act on opioid receptors in the central nervous system, but also mediate clinically less important peripheral effects. Unfortunately, drug tolerance is a problem often encountered in patients receiving prolonged opioid treatment. Furthermore, long-term use of opioids induces physical and psychological addiction, developments not independent of drug tolerance. Both contribute to symptoms associated with opioid withdrawal (OW). Patients who discontinue or strongly reduce opioid administration after long periods of regular use will experience psychiatric symptoms, mainly agitation, anxiety and sleep disturbances, and autonomic nervous system disorders.
OW symptoms may be reduced by replacing the addictive drug with methadone or buprenorphine, both opioids themselves, and requires tapering off these substitution treatments. Psychotherapy and support groups may significantly contribute to the success of the therapy.
Most opioids are strong analgesics or antitussives. Also, illegal drugs like heroin pertain to that class of compounds.
Prolonged intake of moderate to high doses of opioids causes a phenomenon called drug tolerance, i.e., the body adjusts to regular doses of these compounds. However, this body is unable to suddenly undo all these changes if opioid administration is ceased or strongly reduced. The respective patient is physically addicted.
Additionally, opioids mediate a sensation of euphoria. With regards to heroin, this euphoria is also referred to as "kick". This pleasant feeling causes psychological addiction.
If the demands for opioids cannot be fulfilled, the patient will likely experience opioid withdrawal (OW).
Causes
Prolonged opioid treatment may be required in patients suffering from chronic pain. Here, the possible side effects of opioid addiction and OW upon cessation of therapy are largely outweighed by the achieved analgesia. Nevertheless, withdrawal becomes much more bearable with appropriate treatment and should therefore receive medical attention.
The inability to procure supplies leaves those patients addicted to non-prescribed or illegal drugs with OW.
Symptoms
Diagnosis
The patient's medical history is of utmost importance for OW diagnosis. A recent change of therapeutic schemes, a major reduction of opioid doses or prescription of an antagonist prompt suspicion for OW. Thorough clinical examination and laboratory tests will be conducted to detect OW-related symptoms and to rule out other pathological conditions that may account for them.
Treatment
There are two distinct therapeutic approaches to OW. One the one hand, the addictive drug may be replaced with other, less harmful opioids that are subsequently tapered off. On the other hand, symptoms may be alleviated by application of non-opioid drugs. It is strongly recommended to supplement drug therapy with psychotherapy and participation in a support group.