Naloxone Rebound Akathisia: It Could Turn on You

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Overdose deaths involving opioids, including prescription opioids, heroin, and synthetic opioids (like fentanyl), have increased over six times since 1999 and have soared nearly 30% in 2020.

Before the coronavirus pandemic, the nation was struggling with escalating drug overdose deaths. Now, there are some who are convinced that the COVID-19 pandemic has led to further increases in opioid overdoses. Public services were disrupted. Some treatment programs had to restrict access, reduce staffing, and increase supply between limited provider visits. Many addicts are homeless and do not have Internet or telemedicine contact. Social distancing may have prevented some individuals from having anyone around to administer naloxone (Narcan, Evzio). Inadequate border restrictions have likely increased drug supply with higher potency.

These conjoint “opioid epidemics” have heightened and stirred conversations about prescribing and regulatory practices, “war on drugs” rhetoric, the “fifth vital sign,” opioid accessibility, prescription rates, and effectiveness of opioids for non-cancer chronic pain, among many others.

With the rise in opioid use and death, a review of the many and sometimes paradoxical expressions of akathisia is warranted.

As I’ve written in several recent articles, akathisia comprises a family of distressing mental and irresistible motor symptoms fittingly called the dysexecutive function syndrome. Although patients often cannot locate the source of their suffering, it can feel unbearable and lead to suicide. Its associated mental subjective symptoms, which can include irritability, panic, and emotional unease, distinguish it from a dyskinesia. Its causes are legion and often unobvious.

Commonly associated with varying classes of medications, etiologies also include infectious, metabolic, and iatrogenic factors. And there is the potential for admixed categories or cross factor multipliers.

Akathisia symptoms appear in 20% of patients on antidepressants (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclics), 30% to 40% of patients on newer neuroleptics, and 50% to 80% of patients taking first generation antipsychotic drugs. Although the exact neurological circuits remain unknown, the general belief is that there is multiple neurotransmitter system imbalance including basolateral amygdala evolved basal nuclei, locus coeruleus norepinephrine-rich bidirectionality, thalamocortical projections, and alternative endogenous opiate system mechanisms.

Recent epidemiological research indicates that persons taking opioid drugs have a 20% chance of suffering acute akathisia symptoms. Furthermore, drug withdrawal from illegal drugs (intended, imposed, or involuntary) in addition to rapid opioid tapering can also satisfy a troubling and toxic withdrawal akathisia phenotype characterized by significant psychological distress and suicide.

Opioids — a diverse class of illegal, synthetic, and legal pain-relieving compounds — may redistribute the acute risk of drug induced toxic akathisia. That is, in vulnerable individuals, the use of opioids (legally or illicitly) may directly increase the development of this dark and unbearable distress. In other persons, the administration of opioids may temporarily attenuate or suppress its acute development.

However, when overdose resuscitation is critical, and death a likely outcome, it is important to recall that the aforementioned, paradoxical, and unpredictable akathisia-suppressing component of opioid abuse will also be overturned with naloxone administration. Its indicated and necessary emergency use not only reverses central respiratory depressive effects, this medicine may also unsuspectedly cause sudden agitated behavior, feelings of nervousness, restlessness, irritability, and impending doom — symptoms also foretelling de novo akathisia or unmasking concealed akathisia. At this point, the clinician may have yet “another tiger by the tail.”

Therefore, it is important that first responders, emergency clinicians, and addictionologists be aware of this unsuspected and startling “now you see it, now you don’t,” or alternating rising-then-hiding effect (porpoising) of naloxone-induced akathisia. Without an index of suspicion or recognition of context, the use of algorithms or toxidromes will be incomplete. That is, drug use may be obscured not only by the co-ingestion of multiple drugs, but also, the unconventional complications of toxic or mixed akathisia, and its variable iatrogenic or covert masking, reemergence, or intensification.

In fact, this potential for new or latent porpoising is such a tortuous condition that drug-abusing sufferers often panic, and the symptoms magnify the fear. Undeniably, this may lead to the hasty repeating of an illicit dose in an attempt to self-medicate or help the confusing array of symptoms to remit, only to experience rapid overdose respiratory depression and death. Administering a less complicated drug like naloxone is not necessarily less toxic in those susceptible to this adverse reaction.

So, once again, be cautious of the many expressions of akathisia.

Author’s note: This essay does not purport full knowledge, rather, it supplies a guide to this difficult work.

Russell Copelan, MD (Ret.), lives in Pensacola, Florida. He graduated from Stanford University and UCLA Medical School. He trained in neurosurgery and completed residency and fellowship in emergency department psychiatry. He is a reviewer for Academic Psychiatry and founder of eMed International, an originator and distributor of violence assessments. One of Copelan’s four sons is an EMT/paramedic in Colorado Springs, and his daughter is a Denver-based physician assistant.

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