Dexmedetomidine Infusion to Facilitate Opioid Detoxification and Withdrawal in a Patient with Chronic Opioid Abuse

Abstract

Many patients are admitted to the intensive care unit (ICU) for acute intoxication, serious complication of overdose, or withdrawal symptoms of illicit drugs. An acute withdrawal of drugs with addiction potential is associated with a sympathetic overactivity leading to marked psychomimetic disturbances. Acute intoxication or withdrawal of such drugs is often associated with life-threatening complications which require ICU admission and necessitate prolonged sedative analgesic medications, weaning from which is often complicated by withdrawal and other psychomimetic symptoms. Dexmedetomidine, an alpha-2 (α₂) agonist, has been used successfully to facilitate withdrawal and detoxification of various drugs and also to control delirium in ICU patients. Herein, we report a case of a chronic opioid abuse (heroin) patient admitted with acute overdose complications leading to a prolonged ICU course requiring sedative–analgesic medication; the drug withdrawal-related symptoms further complicated the weaning process. Dexmedetomidine infusion was successfully used as a sedative–analgesic to control the withdrawal-related psychomimetic symptoms and to facilitate smooth detoxification and weaning from opioid and other sedatives.

INTRODUCTION

Substance abuse often leads to emergency hospital admission for various life-threatening symptoms. The presenting symptoms are often multiple, misdiagnosed, and often inconsistent because of variable dosage and adulteration of drugs, a mixed intoxication–withdrawal state, and sometimes adverse or idiosyncratic reactions. An acute withdrawal of these illicit drugs is associated with agitation, restlessness, insomnia, generalized muscle and joint pain anxiety, dysphoria, and various psychomimetic disturbances,[1] and most of these symptoms are caused by central nervous system (CNS) hyperactivity and are very distressing which frequently lead to relapse to drug use.[2,3] Acute intoxication and withdrawal of some illicit drugs are often associated with severe and life-threatening complications such as rhabdomyolysis,[4] acute renal failure,[4,5] neurological complication,[5] acute pulmonary edema,[6] ARDS,[6,7] etc., which not only prolonged the intensive care unit (ICU) stay but also made the withdrawal and detoxification process complex. In addition, critically ill patients who received long-term sedative–analgesic therapy in ICU developed functional tolerance and experienced withdrawal symptoms similar to those patients addicted to narcotics, alcohol, or other stimulant drugs.[8–10] So far we do not have standard guidelines or recommendations on the use of sedation-analgesia in patients with drug addiction problems or who are prone to have addiction potential.

Dexmedetomidine has been gaining popularity in controlling withdrawal symptoms associated with varieties of substance abuse and dependences and has been successfully used to facilitate withdrawal of prolonged sedation in ICU.[1,2,10–14]

We are reporting a case of an acute, severe overdose of an opioid (heroin) in an opioid addict complicated by rhabdomyolysis leading to acute renal failure and later development of adult respiratory distress syndrome (ARDS) which leads to a prolonged ICU stay in which prolonged dexmedetomidine was used to facilitate the withdrawal process.

CASE REPORT

A 32-year-old male, addicted to heroin for 3 years, was found in a semiconscious, unresponsive state in his room and brought in a state of shock with gasping respiration by family members to the emergency room. He was hypothermic, hypotensive with blood pressure 70/45 mmHg, a heart rate of 128 per min, shallow respiration with a rate of 12/min, and hypoxemic with oxygen saturation 88% on 10 liter per min oxygen. Initial evaluation was suggestive of an acute opioid overdose as the patient was a known heroin addict; there were pinpoint pupils with hypoventilation and hypothermia. A blood sample was sent to the toxicology laboratory. After 0.4 mg of intravenous naloxone in increments of 0.1 mg boluses, patient's sensorium level improved and respiration became more normal with an improvement in oxygen saturation, but he remained hypotensive. Fluid resuscitation was continued, vasopressor (noradrenaline infusion) added, and an infusion of naloxone was started. The patient was shifted to the ICU for further observation and treatment. Blood gas analysis showed persistent metabolic acidosis. Hematological parameters were normal but biochemistry revealed signs of acute rhabdomyolysis with a marked rise in the creatinine kinase level, hyperkalemia, and high blood urea nitrogen (BUN) and creatinine. Aggressive hydration with alkalinazation and forced diuresis was started. Despite the aggressive therapy for about 3 h, the patient went into anuria with a marked rise in creatinine. The patient started to agitate, and become restless with a complaint of generalized body and joint pain and his respiration became labored; auscultation revealed bilateral diffuse crepitation. The patient was intubated and connected to a mechanical ventilator with propofol and remifentanil infusion as sedative-analgesic. An urgent chest X ray confirmed acute pulmonary edema. Nephrology consultation was sought for urgent dialysis; naloxone infusion was stopped. Although the metabolic parameters improved after urgent dialysis, the ventilatory parameters worsened requiring higher amounts of oxygen and a higher level of positive end expiratory pressure (PEEP). Echocardiographic evaluation revealed a normal cardiac function. The lung condition worsened further over the next couple of days with severe hypoxemia consistent with ARDS. The patient was managed with a lung protective ventilatory strategy with the infusion of methyl prednisolone 1 mg/kg/day along with other supportive care in the form of regular dialysis, antibiotics, nutritional support, chest physiotherapy, etc. In view of the prolonged ventilatory support, the sedation-analgesia regime was changed into midazolam and morphine. After about 10 days, respiratory parameters were gradually improved, and the kidney function started to recover. The patient was successfully extubated and liberated from the ventilator when he passed the spontaneous breathing trial (SBT) on day 15. Few hours after extubation, the patient started to show signs of opioid withdrawal with agitation, generalized aches and pain all over the body, lacrymation, increasing restlessness, tachypnea, tachycardia, and hypertension. The trial of intravenous haloperidol failed to control his agitation. He was reloaded with a short-acting opioid, remifentanil, to which he responded; psychomimetic and other physical symptoms were modestly controlled with 400 μg/h of remifentanil, but he required increasing doses of remifentanil and was restless and agitated on the slightest reduction of remifentanil infusion. The trial of midazolam and propofol infusion failed to reduce the remifentanil requirement. On day 18, dexmedetomedine infusion was added after a loading dose of 50 μg over 30 min, and remifentanil infusion was successfully tapered off over 4 h. The patient was managed with a continuous infusion of dexmedetomidine 0.7 μg/kg/h, and lorazepam was added for night comfort. On day 5 of dexmedetomidine infusion, we gave oral clonidine 25 μg every 4 h to the patient and slowly tapered off dexmedetomidine over the next 2 days. He remained conscious, oriented, and calm throughout the dexmedetomidine treatment. Finally, he was shifted to a rehabilitation center on oral clonidine.

DISCUSSION

One of the problems encountered while treating critical illness in patients on ventilators who are already addicted to opioids or other drugs of abuse is the development of dependence and withdrawal process itself; these patients are prone to develop delirium in ICU. Unfortunately, the drugs of choice such as benzodiazepine and opioids are similar to ones that are abused. Once patient's primary condition improved, a smooth withdrawal of the sedative–analgesic without psychomimetic symptoms became the limiting factor for the recovery of the patient. An alpha-2 (α ₂) agonist has been successfully used to attenuate the hypertension, tachycardia, agitation, anxiety, and fever occurring during the withdrawal of benzodiazepine and the opioid.[14–18] Clonidine has been used to attenuate the symptoms of withdrawal from alcohol, narcotics, and naloxone-induced hypertension for more than 20 years. Dexmedetomidine, a selective α₂-adrenergic agonist with an affinity eight times more than that of clonidine, results in more selective α₂ activation and exerts the desired effects of sedation, analgesia, anxiolysis, and sympatholysis with less respiratory depression[13] and negligible effects on α ₁stimulation,[19] and it has been used to facilitate the withdrawal of various drug dependencies such as alcohol,[20,21] cocaine,[17,22] opioid,[11,12,19] and benzodiazepine.[12] It has also been used successfully even in infants to detoxify opioid and benzodiazepine sedation.[12]

The mechanism of dexmedetomidine in controlling the withdrawal of opioids is poorly understood but it is hypothesized that the withdrawal from narcotics is characterized by a hyperadrenergic state: the α₂ agonist decreases the sympathetic outflow and adrenergic activity counteracting the physiological effects of the withdrawal and these effects are largely mediated by postsynaptic α_2A subtype receptors in the locus ceruleus.[23–25] The α₂ agonist and opioid act synergistically on the central sympathetic outflow.[26] The mechanism of how dexmedetomidine enhances the opioid analgesia is not yet clear. The potentiating effects of the α₂ agonist on morphine reduce the amount of the opioid needed and a low dose of the opioid may be effective for a long period.[27] There are some evidences that the α₂ agonist induced antinociception results by the acetylcholine release inhibiting nociceptive neurons in the spinal cord.[27]

In summary, our observation suggests that dexmedetomidine infusion facilitated the opioid withdrawal and control of opioid withdrawal symptoms in an opioid-dependent patient without causing either significant neurological or respiratory depression. Dexmedetomidine may also be useful in the management of opioid-induced hyperalgesia and iatrogenic-induced tolerance seen in patients maintained on opioid therapy for chronic painful conditions. A further study with a larger sample size is needed to explore its potential in the management of opioid tolerance or dependence and also to facilitate opioid withdrawal.