Opioid addiction affects 15.5 million people in the world, including 11.1 million heroin users (WHO) (United Nations Office on Drugs and Crime, 2007) [1]. Although in the USA, opioid prescriptions rose between 2002 and 2010 but have been decreasing since 2013, owing to physicians’ awareness of a rise in the opioid-related death rate and the increase in opioid medications [2]. Consequently, these patients need to end their misuse of opioids, but the mild to severe clinical symptoms associated with opioid withdrawal risk increasing the pain already present. Such symptoms are dysphoria, restlessness, rhinorrhea, lacrimation, myalgias, arthralgias, nausea, vomiting, abdominal cramps, diarrhea, yawning, increased flatulence and piloerection. Accordingly, in cases of severe somatic or psychiatric withdrawal symptoms, it might be preferable to manage opioid withdrawal when patients are hospitalized (Guidelines for the management of opioid withdrawal, WHO, 2009) [3]. There is a risk of complications such as distress, increased heart rate, high or low blood pressure. Anxiety, depression and, more rarely, psychotic episodes have been described when opioids are stopped suddenly [4–6]. Opiate withdrawal may be done gradually, using opiate substitution drugs such as methadone or buprenorphine, or abruptly. In the latter case, withdrawal symptoms are managed with adjunctive medication such as clonidine and benzodiazepine, and medication to treat the symptoms. Clonidine binds to a central alpha 2 adrenergic receptor that shares potassium channels with opioids and blunts withdrawal symptoms. In addition to clonidine, benzodiazepines and other GABAergic drugs reduce catecholamine release during severe withdrawal, and the benzodiazepines themselves have been shown to reduce withdrawal symptoms in animal models [7, 8]. Symptomatic medications such as loperamide, phosphoglucinol, and octreotide could be added for gastro-intestinal symptoms. Thus, managing opiate withdrawal requires multiple prescriptions, with a high risk of drug-drug interaction and incomplete patient relief, a particularly sensitive issue in the case of patients taking opioid drugs in the context of pain associated with somatic disease.

In such cases, it might be worth investigating whether ketamine, widely used by anaesthetists to limit opioid tolerance, reduce use of painkillers, and increase the time preceding the first request for painkillers during the postoperative period [9], may be efficient for managing opioid withdrawal. Ketamine has also shown it has a role to play as an anti-hyperalgesic and tolerance-protective drug. It is acknowledged that it is of interest for managing various pain conditions, such as pain connected with opioid tolerance, acute pain or chronic pain [10–12]. Pain physicians use ketamine at sub-anaesthetic doses to treat refractory chronic pain syndromes, especially cancer- and non-cancer-related pain, or pain with a neuropathic component [13–15]. Moreover, recent publications showed that use of alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan could minimize tolerance development during opioid treatment [16]. As well as the tolerance effect, it is well known that chronic opioid medication can potentially increase subjective pain when prescribed for a long period [17]. Chronic treatment with opioids may also be complicated by abnormal pain sensitivity such as opioid-induced hyperalgesia [18, 19]. In cancer pain patients who have lost an analgesic response to high doses of opioids, a synergistic effect between oral ketamine and opioids and a rightward shift of the opioid-response curve were observed [20].

Ketamine is classified as an NMDA receptor antagonist but has many other pharmacological actions on mu, delta, kappa opioid receptors and monoamine transporters, inhibiting serotonin, dopamine and norepinephrine reuptake. Low doses of ketamine reduce morphine use, nausea and vomiting after surgery [21, 22], an effect mediated by NMDA antagonism plus μ-opioid and sigma receptor activation. In the central nervous system, ketamine, like other NMDA receptor antagonists, triggers anesthetic, amnesic, dissociative, and hallucinogenic effects. Activation of κ-opioid receptors and possibly sigma and mACh receptors may also contribute to its psychotomimetic properties [21]. Dopamine and serotonin reuptake inhibition is likely to underlie an antidepressant effect which is clinically relevant in depressed patients [23], although an additional but weak action of μ-opioid receptor activation cannot be ruled out [21]. In peripheral systems, ketamine enhances catecholaminergic transmission, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems [24], increasing sympathetic stimulation of the cardiovascular system, and reducing nausea and vomiting and respiratory complications like bronchoconstriction. However, ketamine side effects may induce aberrant percepts, including musical and auditory verbal hallucinations [25], and its repetitive administration may lead to the development of additive behavior [26, 27]. Accordingly, its use in medical care should be strictly supervised.

Some studies looked at the effect of ketamine for managing opioid withdrawal in the case of precipitated opiate withdrawal. One study, involving 58 patients who underwent rapid opiate antagonist induction under general anesthesia, showed that ketamine could help manage opioid withdrawal [28]. Prior to opiate antagonist induction, patients were given either a placebo (normal saline) or subanaesthetic ketamine infusion of 0.5 mg/kg/h. The ketamine group presented better control of withdrawal symptoms, lasting beyond the ketamine infusion itself. Significant differences were noted between the ketamine and control groups in the anaesthetic and early postanaesthetic phases, but no differences in effects were observed in terms of outcome after 4 months. In the same year, a Japanese team reported the case of a 2 year-old girl who received ketamine perfusion to manage symptoms caused by opioid withdrawal precipitated by naloxone [29]. To the best of our knowledge, there is no literature on ketamine use in opioid withdrawal not precipitated by naloxone. Here we report, according to the CARE (CAse REport) guidelines [30], the case of a 36 year-old woman hospitalized for opioid painkiller addiction who was treated with ketamine for the purpose of opioid reduction and withdrawal.