A cautionary tale: Smart people and addiction

Rationalization and denial are key concepts in addiction treatment. To recover, addicts admit they have rationalized their habit („I use so much less than my friends.“) and denied they have a problem („I can handle it. It’s not affecting my job.“)
Here’s another barrier to recovery from addiction: „I’m too smart for this to become a problem.“

This week’s Journal of the American Medical Assn., contains a sad essay from a medical researcher who made headlines last year when his fiancee, also a medical researcher, died after the two injected themselves with what they thought was the narcotic buprenorphine for kicks.

The author of the essay, Clinton B. McCracken, a former pharmacologist at the University of Maryland, describes how he became a user of marijuana and intravenous opioids (morphine and oxycodone) over a decade while building his career as a successful neuroscientist who studied the effects of drugs on the brain.

He notes that people who work in medicine have addiction rates that are equal to, if not higher than, rates among the public. Drugs are easier to get, McCracken said. But he said an attitude of arrogance led him, as a medical professional, to believe that he could enjoy dangerous drugs and avoid serious consequences. For example, he was careful to schedule his opioid use to prove to himself that he did not need it to get through the day, made sure he was tending to his responsibilities at work and reviewed the criteria for drug dependence to assure himself that he was not an addict.

„By intellectually addressing the official criteria for abuse and dependence, I provided myself with the illusion of total control over the situation and was able to confidently tell myself that no problems existed,“ he wrote in the essay.

His world came crashing down last fall when his fiancee died while injecting Drugs with him. When the police arrived, they discovered McCracken’s Mariuhana plants. He was arrested and jailed, and he later agreed to a plea bargain to avoid more serious charges. Besides losing his girlfriend, he has since lost his career, his reputation and, as a citizen of Canada and convicted felon, he expects to be deported.

Addiction may look different in different people, but it seems that, in the end, everyone, no matter the level of intelligence, looks the same — ruined.

„The transition from my drug use having no apparent negative consequences, to both my personal and professional life being damaged possibly beyond repair, was so fast as to be instantaneous, highlighting the fact that when it comes to drug use, the perception of control is really nothing more than an illusion,“ he wrote.

— Shari Roan
May 20, 2010

Here is the „sad essay“ :

Health care professionals and physicians in particular have rates of substance abuse that are equal to and often exceed those observed in the general public.These estimates may even be low, as many studies rely on self-reported data. Health care professionals presumably use drugs for many of the same reasons as those of the general population.

Nonetheless, given the intelligence, years of education, and high levels of achievement found in this group, the relatively high incidence of substance abuse may be somewhat surprising. Ease of access to drugs is commonly cited, particularly with respect to the high rates of drug abuse among anesthesiologists; however, given the complex nature of addiction, the underlying causes are assuredly myriad.

One possible contributing factor that may receive insufficient attention is the ability of highly educated professionals to intellectualize their drug use, minimizing in their mind the potential disastrous consequences, both personal (eg, the possibility of death or serious harm due to factors such as overdose or toxicity, among others) and professional (ranging from a tarnished reputation to a ruined career). This intellectualization is particularly insidious because due to its very nature, it prevents the person from realizing the scope of the problem, or even admitting a problem exists. Thus, it is related to, yet distinct from, the phenomena of rationalization and denial. Rationalization and denial are universal components of substance abuse and unaffected by education or training.

By contrast, intellectualization actually relies on advanced education and training, particularly with respect to the effects of drugs and addiction, also incorporating confidence in one’s intelligence and abilities, and no small measure of arrogance, to provide the illusion of control or mastery. The end result of this intellectualization is the manifestation of hubris that produces blindness to the devastating consequences of drug abuse and addiction.

Here, I draw on my experience as a drug abuser who for years maintained a relatively successful career as a basic biomedical scientist studying the neuroscience of addiction and compulsion to present a cautionary tale regarding the extreme dangers of intellectualizing drug use. No matter how well versed one may be in pharmacology or the addictive process, the fact remains that severe problems due to drug abuse can arise almost instantly, and no matter how in control one may believe himself to be, these problems can lead to tragic and irreversibly life-altering consequences.

In my case, this intellectualization occurred on three main levels.

The first related to my drug use patterns. I was a daily user of cannabis for most of the past decade, and an intermittent user of opioids, primarily via the intravenous route, for approximately three years. This use occurred while I pursued a career in basic science research, with a heavy focus on addiction. Consequently, I was intimately familiar with the drug abuse literature and psychiatric diagnostic manuals such as the DSM-IV. I was able to finish my doctorate and conduct research at a high level at the same time I was a regular drug user.

Mindful of the DSM-IV criteria for substance abuse and dependence, I was able to rationalize my drug use in a number of different ways, all with the similar end result of deluding myself into thinking I did not have a problem. First among these was that I was able to maintain a high level of professional achievement while using drugs. In addition, I was able to form and maintain a number of fulfilling personal relationships over this time period. As such, I felt that I was not suffering dire consequences in my personal and professional lives. I was able to tell myself that those items on the DSM-IV clearly did not apply to my situation, and hence no problem existed. I used similar reasoning for other items on the DSM-IV checklists for substance abuse and dependence.

I identified my daily marijuana use as „stable“ for some time (ie, years), and I was able to cease use for weeks at a time without any serious difficulty. Thus, any worries of tolerance (ie, increased use over time) or dependence (ie, withdrawal symptoms upon cessation of use) were minimized. With respect to opioids, I was keenly aware of the potential for these drugs to produce tolerance and dependence and thus restricted my use to no more than two consecutive days spaced no closer than 2 or 3 months apart.

By intellectually addressing the official criteria for abuse and dependence, I provided myself with the illusion of total control over the situation and was able to confidently tell myself that no problems existed. This was in spite of the fact that my ongoing drug use was jeopardizing not only my health, but my career.

I was also able to intellectually justify using opioids via the intravenous route. My first experience with opioid medication came after they were prescribed for pain following an injury. I enjoyed the effects and began to seek other sources to attain these drugs. Although I was acutely aware that these drugs had strong potential to cause tolerance and dependence, I was secure in my ability to control the situation. So why inject? I initially began using these drugs via the IV route primarily to maximize bioavailability.

Many opioids, and morphine in particular, possess only a fraction of their IV bioavailability when taken orally. The euphoria due to rapid drug onset via the IV route (ie, the „rush“) was another attractive factor. While I was aware that IV use presented dangers when compared with oral administration, such as increased risk of overdose, infection, or embolism, I was confident that my technical experience (having performed injections into small-animal blood vessels) and access to sterile needles, sterile syringes, sterile saline as a diluent, and alcohol swabs would allow me to circumvent many of the typical problems associated with IV administration. In hindsight, in my overconfidence I minimized one of the key dangers of IV use—the fact that the extremely rapid onset can lead to irreversible effects if things should happen to go wrong.

The final method by which I was able to intellectualize my drug use dealt with the means by which I obtained drugs. I rationalized that small-scale marijuana cultivation was less risky than purchasing it and was associated with a relatively minimal risk of discovery and associated arrest. I obtained opioids (primarily morphine and oxycodone) from an overseas online pharmacy. In addition to less risk of arrest, I made the assumption that dosage would be more consistent and the chance of adulteration much lower than drugs purchased on the street, thus reducing the risk of possible overdose. Furthermore, in the initial stages of opioid use, I proceeded extremely cautiously to ensure the drugs I received from overseas were what they purported to be. After satisfying myself that this was indeed the case, at least at the beginning, I assumed that this form of quality control was no longer necessary.

There were no acute problems stemming from my drug use for approximately three years. My fiancée, a successful scientist in her own right, and with whom virtually all of my intravenous drug use occurred over the previous three years, lost her life after injecting a product that produced severe anaphylaxis, most likely due to some form of contamination. While waiting for the paramedics to arrive I tried unsuccessfully to resuscitate her. Despite heroic efforts, neither the paramedics nor the emergency department physicians were able to revive her.

As a consequence of her death, our house was searched by police, who then discovered the ongoing marijuana cultivation. I was immediately arrested, jailed, and charged with a number of felonies; then, in the space of a few days, my employment as a postdoctoral fellow was summarily terminated and I was evicted from my residence.

The impact of these events on my life has been enormous. First and foremost is the loss of the woman I loved, my best friend and partner, with whom I had planned to spend the rest of my life. Not only were we a team in the sense of personal life, but also professionally. We worked in the same field, attended the same meetings, and were well known as a couple in our part of the scientific community. Thus, my relationship with her came to define all aspects of both my work life and my home life.

Coming to terms with her loss has proven to be extremely challenging and will likely remain so for a long time. While paling completely compared to the loss of my fiancée, I face a number of other consequences. For one, my career as an academic research scientist has been undeniably derailed, if not destroyed. Reputation is critical in my field, and mine is likely to be damaged for the foreseeable future. I originally faced substantial time in prison; I was able to agree to a plea bargain whereby I avoided any additional incarceration. However, I have now been convicted of a felony, which will undoubtedly have a severely negative effect on any future job prospects and international travel. Finally, as a Canadian citizen, my ability to live in, work in, and even visit the United States, my home for the last ten years, is also compromised; I face imminent deportation with almost no hope of reentry in the future.

The transition from my drug use having no apparent negative consequences, to both my personal and professional life being damaged possibly beyond repair, was so fast as to be instantaneous, highlighting the fact that when it comes to drug use, the perception of control is really nothing more than illusion. Had these events not occurred as they did, it is possible, even probable, that my drug use would have escalated until it precluded a normal personal or professional life.

However, it is important to note here that problems associated with drug abuse can arise with devastating effects even in the apparent absence of many diagnostic criteria, such as overt tolerance and dependence.

Neither advanced education nor knowledge of pharmacology nor familiarity with the addictive process was able to prevent tragic consequences for me. It is my sincere hope that my experience may serve as a warning, help illuminate the dangers of intellectualizing drug use and abuse, and prevent similar tragedies in the lives of others.

Additional Contributions: I thank Lawrence R. Fishel, PhD, and Anthony A. Grace, PhD, for their comments and assistance with this article.

Morphine makes lasting — and surprising — change in the brain

Morphine, as little as a single dose, blocks the brain’s ability to strengthen connections at inhibitory synapses, according to new Brown University research published in Nature

The findings, uncovered in the laboratory of Brown scientist Julie Kauer, may help explain the origins of addiction in the brain. The research also supports a provocative new theory of addiction as a disease of learning and memory.

„We’ve added a new piece to the puzzle of how addictive drugs affect the brain,“ Kauer said. „We’ve shown here that morphine makes lasting changes in the brain by blocking a mechanism that’s believed to be the key to memory making. So these findings reinforce the notion that addiction is a form of pathological learning.“

Kauer, a professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown, is interested in how the brain stores information. Long-term potentiation, or LTP, is critical to this process.

In LTP, connections between neurons – called synapses, the major site of information exchange in the brain – become stronger after repeated stimulation. This increased synaptic strength is believed to be the cellular basis for memory.

In her experiments, Kauer found that LTP is blocked in the brains of rats given as little as a single dose of morphine. The drug’s impact was powerful: LTP continued to be blocked 24 hours later – long after the drug was out of the animal’s system.

„The persistence of the effect was stunning,“ Kauer said. „This is your brain on drugs.“

Kauer recorded the phenomenon in the ventral tegmental area, or VTA, a small section of the midbrain that is involved in the reward system that reinforces survival-boosting behaviors such as eating and sex – a reward system linked to addiction. The affected synapses, Kauer found, were those between inhibitory neurons and dopamine neurons. In a healthy brain, inhibitory cells would limit the release of dopamine, the „pleasure chemical“ that gets released by naturally rewarding experiences. Drugs of abuse, from alcohol to cocaine, also increase dopamine release.

So the net effect of morphine and other opioids, Kauer found, is that they boost the brain’s reward response. „It’s as if a brake were removed and dopamine cells start firing,“ she explained. „That activity, combined with other brain changes caused by the drugs, could increase vulnerability to addiction. The brain may, in fact, be learning to crave drugs.“

Kauer and her team not only recorded cellular changes caused by morphine but also molecular ones. In fact, the researchers pinpointed the very molecule that morphine disables – guanylate cyclase. This enzyme, or inhibitory neurons themselves, would be effective targets for drugs that prevent or treat addiction.

Ouch! Abrupt opioid withdrawal increases pain sensitivity!

(PhysOrg.com) — The abrupt withdrawal of morphine-like analgesics – opioids – can increase sensitivity to pain. Experiments have now shown that this effect is caused by a memory-like process, the long-term potentiation of synaptic strength in the spinal cord. The study, which was supported by the Austrian Science Fund (FWF), also found ways of avoiding this increase in pain sensitivity. These pioneering results have now been published in the prestigious journal Science.

Opioids are the oldest and most effective analgesics. They are often used, for example, during operations or when other forms of treatment fail. This is because opioids – unlike other analgesics – bind to opioid receptors, which are highly effective in depressing the activity of nerve cells responsible for transmitting information about pain. On abrupt withdrawal, e.g. after surgery, this can lead to an abnormal, excessive increase in pain sensitivity. A research project conducted by the Department of Neurophysiology at the Center for Brain Research at the Medical University of Vienna has now been able to explain what causes this phenomenon.

Painful „cold withdrawal“

The abrupt withdrawal („cold withdrawal“) of opioids leads to „long-term potentiation“ (LTP) of synaptic strength in the spinal cord’s pain pathways. This in turn leads to sustained and increased sensitivity to pain. In the brain, LTP is a physiological mechanism for learning and memory. An activity-dependent increase in synaptic transmission between the nerve cells at their contact points, the synapses, can be very long-lasting. For example in the spinal cord, pain stimuli can trigger LTP and lead to a long-lasting „pain memory“. This study proves for the first time that opioids also leave a „memory trace“ in the pain system if they are withdrawn abruptly. „We were rather taken aback ourselves by the results,“ said project manager Professor Jürgen Sandkühler. „Until now, we had assumed that only strong or sustained pain could induce LTP in the pain system.“ On making this discovery, Prof. Sandkühler and his team set about deciphering the molecular mechanisms of this process. Dr. Ruth Drdla and Matthias Gassner, the two main authors of the study, were able to show that abrupt withdrawal – similar to a pain stimulus – increases the concentration of calcium ions in the spinal cord’s nerve cells.

Excessive calcium ions

Calcium ions are important intracellular messengers that activate numerous enzymes and consequently also lead to LTP. With memory LTP, calcium ions flow into the brain’s nerve cells via NMDA receptor channels. Therefore, the research team conjectured that blocking these calcium channels could also prevent LTP in the spinal cord. „To test our theory, we used selective blockers that only close off NMDA receptor-type calcium channels,“ explains Prof. Sandkühler. The results showed that these blockers, which are also available as drugs, did indeed reliably prevent LTP on the withdrawal of opioids. „However, the blocker has to be administered in good time before the start of the withdrawal,“ adds Prof. Sandkühler. The team also made another discovery that is important for the treatment of pain: If the opioid is reduced slowly and in a controlled
manner instead of being withdrawn abruptly, it is quite straightforward to prevent the LTP caused by opioid withdrawal and, therefore, the onset of withdrawal symptoms.

This latter result of the FWF-supported project in particular shows that fundamental medical research can indeed provide concrete recommendations for everyday medicine. These new findings mean that essential opioids can be applied even more reliably in the treatment of pain – without any nasty surprises once they are withdrawn.

More information: Ruth Drdla, Matthias Gassner, Ewald Gingl and Jürgen Sandkühler. Induction of synaptic long-term potentiation after opioid withdrawal, Science 325 (2009), July 10th. DOI: 10.1126/Science/1171759.

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Opioids, sleep architecture and sleep-disordered breathing

Opioid use whether acute or chronic, illicit or therapeutic is prevalent in Western societies. Opioid receptors are located in the same nuclei that are active in sleep regulation and opioid peptides are suggested to be involved in the induction and maintenance of the sleep state. mu-Opioids are the most commonly used opioids and are recognized respiratory depressants that cause abnormal awake ventilatory responses to hypercapnia and hypoxia. Abnormal sleep architecture has been reported during the process of opioids induction, maintenance and withdrawal. During induction and maintenance of opioid use there is reduction of rapid eye movement (REM) sleep and slow wave sleep. More recently, central sleep apnoea (CSA) has been reported with chronic opioid use and 30% of stable methadone maintenance treatment patients have CSA. Given these facts, it is sobering to note the paucity of human data available regarding the effects of short and long-term opioid use on sleep architecture and respiration during sleep. In this manuscript, we review the current knowledge regarding the effects of mu-opioids on sleep and respiration during sleep and suggest research pathways to advance our knowledge and to explore the possible responsible mechanisms related to these effects.

Opioid use whether therapeutic or illicit is common worldwide. In year 2000, approximately 1.2% of the American population reported heroin use at least once in their lifetime.¹ In Australia, the estimate of recent illicit opioid users was 0.6% of the 14 yrs and older population in 2001 compared to 1% in 1998.2 Australian Institute of Health and Welfare. 2001 National Drug Strategy House Hold Survey: first results. Canberra, Australia, 2002.² More than 140,000 patients were receiving methadone maintenance treatment (MMT) in 1998 in the United States,³ and in Australia 30,000 were receiving MMT in year 2000.⁴ Opioids are also commonly used for acute and chronic pain management and as an adjunct to anaesthesia and occasionally for the restless legs syndrome.^{5 and 6} An American study reported that 80% of 2118 cancer patients referred to a pain service were prescribed opioids.⁶ In year 2004, there were more than 410,000 registrants for opioid use in American pharmacies compared to around 390,000 in 1997.⁷ The average gram weight per registrant increased 7.3 fold for oxycodone, 5 fold for methadone, 4.6 fold for fentanyl base and 3 fold for hydrocodone from 1997 to 2004.⁷ Prescribed opioids related deaths account for most of non-illicit drug poisoning deaths in America and the problem has been increasing in the past decade.⁸ Abuse of opioid analgesics is very common and in 2005, 9.5% of American 12th graders reported using Vicodin and 5.5% of these students reported using OxyContin in the past year.⁹

Many opioid receptors are located in the same nuclei that are active in sleep regulation¹⁰ and it has been suggested opioid peptides are involved in the induction and maintenance of the sleep state.¹¹ Chronic opioid use has been hypothesized to cause disturbed sleep as well as excessive day-time sleepiness and fatigue.¹² A few studies have reported abnormal sleep architecture in opioid users but most were performed prior to 1990 and few tested breathing during sleep though opioids are well-known respiratory depressants.⁵ In recent studies, central sleep apnoea (CSA) has been found in stable MMT patients and in patients prescribed time-release opioid analgesic management.^{13, 14 and 15} Abnormal ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) have also been noted in stable MMT patients.¹⁶ Infants born to substance-abusing mothers have a higher prevalence of periodic breathing during sleep and a 5–10 times increased risk of sudden infant death syndrome (SIDS) compared to normal infants.^{17 and 18} The potential symptoms and other sequelae related to CSA and periodic breathing have not been discussed in reviews of opioid use for chronic pain or in methadone substitution programs.⁶

Morphine-like μ-opioids are clinically the most commonly used opioids and this review focuses on their effects on sleep and respiration during sleep in humans. Where evidence is available, we will discuss the pathogenesis of abnormalities described and will also discuss future research directions given the considerable lack of knowledge in this important area of medicine. The scope of this review includes sleep and respiration during sleep in acute and chronic opioid analgesic use, opioid abuse and in MMT programs.

Opioids and control of sleep

There are four major classes of endogenous opioid receptors in the central nervous system: μ, δ, κ and nociceptin/orphanin FQ (N/OFQ) receptor.⁵ Each of these receptor subtypes has a distinct profile in terms of its pharmacology as well as its distribution within the brain and spinal cord. Most of the clinically used opioids are relatively selective for μ receptors, such as morphine and methadone.⁵ It appears that REM suppression is associated primarily with the actions of μ-opioid receptor agonists.¹⁹ Three classes of opioid peptides have been identified: the enkephalins, endorphins and dynorphins.⁵ These have been shown to have a role in sensory modulation and analgesia and may be important in the onset and maintenance of sleep, and therefore be involved in attenuation of arousal and waking.²⁰ Enkephalin is contained in neurons that are widely distributed through the brain and regions involved in slow wave sleep (SWS) such as the solitary tract nucleus, the preoptic area and the raphe, where it is colocalized with serotonin receptors.²⁰ Enkephalin containing fibres innervate the locus coeruleus noradrenergic neurons which are inhibited by locally delivered opioids and produce decreased awakenings and increased SWS.²⁰ β-Endorphin is derived from prepro-opiomelanocortin (POMC) which is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (α-MSH) and β-lipotropin (β-LPH).⁵ ACTH is the hormone closely related to stress and α-MSH has been suggested to induce sleep and increase SWS. The association of sharing the same precursors implies a close physiological linkage between stress, sleep and the opioid systems.⁵

The mechanism of opioid peptide action on sleep control remains unclear. It has been hypothesized that opioid peptides in conjunction with the peptide neurohormone vasopressin are involved in the induction and maintenance of the sleep state through a complex and modifiable circadian mechanism driven by the suprachiasmatic nuclei (SCN).¹¹ Vasopressin, one of the neurohormones in the circadian pacemaker SCN, has been shown to have a close relationship to circadian rhythms.²¹ Vasopressin causes the secretion of endorphins into the cerebro–spinal fluid (CSF), while pain and opioids stimulate the secretion of vasopressin from the pituitary.²² In the supraoptic and paraventricular nuclei, vasopressin is stored with the opioid peptide dynorphin which also shows circadian variability of its blood levels.²³ It is possible that both vasopressin and the opioids are part of the neurochemical mechanism driven by SCN to maintain the daily sleep and wake rhythm.¹¹

Exogenous opioids may affect the activity of opioid receptors by binding to the same sites as those of endogenous opioid peptides.²⁴ Endogenous enkephalin production is linked by a negative feedback mechanism to the serum level of opioids which are high in chronic opioid users.²⁵ Given the possible links between endogenous opioids and control of sleep previously discussed, it is reasonable to suggest that acute and chronic opioid use may have an effect on sleep hygiene and sleep architecture.

Opioids and control of respiration when awake and during anaesthesia

In humans, the primary opioid receptors involved in control of respiration are assumed to be μ-receptor type.⁵ δ-Receptors may exert modest respiratory depressant effects, whereas κ-receptors have little respiratory depressant activity.²⁶ Acute use of μ-receptor stimulating opioids can cause dose dependant depression of respiration.⁵ Opioid receptors in brain stem (medulla, pons, nucleus tractus solitarius, and nucleus ambiguous), spinal cord, and peripheral sites such as lung tissue are involved in the respiratory depression. However, the brain stem respiratory centres predominate with regard to this effect.^{5, 26 and 27} Both HCVR and HVR can be significantly reduced by acute use of opioids.^{26 and 28} Opioids can also blunt the increase in respiratory drive normally associated with increased loads such as increased airway resistance.²⁷ Acute opioid use may cause increased respiratory pauses, delays in expiration, irregular and/or periodic breathing and decreased/normal tidal volume.²⁷ The prolonged expiratory time in the respiratory cycle induced by opioids often results in greater reductions in respiratory rate than in tidal volume.²⁶ Increased tidal volume variability was reported to be a better predictor of respiratory depression than a fall in respiratory rate when remifentanil was infused during dental anaesthesia.²⁹

Waters et al. studied 13 children with OSA and 24 normal subjects undergoing tonsillectomy.³⁰ They found that under inhalational anaesthetic and spontaneous ventilation, the OSA group hypoventilated and tended to have higher end tidal CO₂ levels than the normal group. Following fentanyl injection, 6 of the OSA group exhibited central apnoea compared with one of the normal subjects. The production of central apnoea post opioid injection in both groups was related to end tidal CO₂ higher than 50 Torr.³⁰ Though this study has methodological flaws, the data suggests that at least in children, subjects prone to hypoventilation may progress to central apnoea when given a μ-opioid, however, whether this equates to CSA in these children is unknown.

With long-term use of opioids, subjects have reduced HCVR although tolerance appears to develop.^{16 and 31} An early study assessing HVR in MMT patients suggested blunting of HVR in both the acute and chronic stages of methadone use.³¹ However, this study should be interpreted with caution as there was no baseline data from normal subjects available for comparison.³¹ In contrast, in our study of stable MMT patients, HVR appears to be increased (Fig. 1).¹⁶ The causes for this finding are not clearly known and may relate to long-term stimulation of the hypoxic response by long-term intermittent hypoxia.¹⁶ The high HVR and low HCVR we found in the stable MMT patients related to changes in respiratory rate and not tidal volume response.¹⁶

Opioid use, sleep and respiration during sleep

Given the large opioid using population and the possible close link between endogenous opioids and control of sleep, there is a scarcity of studies investigating sleep in human adult subjects using opioids.¹² There are studies assessing sleep in animals that show changes in sleep architecture with acute and chronic μ-opioid use.^{32 and 33} We were unable to find data related to effects of chronic use of μ-opioids on respiration during sleep in animals. Breathing during sleep in human subjects using opioids has been poorly studied despite the fact that the commonly used μ-opioids are known to depress respiration and sleep-disordered breathing in its own right can significantly affect sleep architecture.⁵

Table 1 shows the findings and methodologies of 18 human studies available on PUBMED published between 1966 and 2005 investigating sleep and respiration during sleep in adult humans using opioids. We cite only those studies using objective measurements and reported in English. Studies assessing the effects of opioids on sleep and respiration during sleep in post-operative surgical patients and restless legs syndrome patients are not included in the table. Restless legs syndrome itself can significantly disturb sleep and the studies in the anaesthetic literature are often confounded by poor patient selection, use of concomitant anaesthetic agents, analgesics and post-operative pain. In addition, natural sleep is clearly different to anaesthesia which is a state of unrousable unconsciousness.³⁴ During anaesthesia, there is dose-dependant depression to most of the vital functions including respiration.³⁴ Abnormal breathing patterns in anaesthesia are different to sleep-disordered breathing although the tendency to upper airway obstruction during sleep and during anaesthesia are probably related.³⁵ Of the studies listed in Table 1, 16 used morphine like μ-opioids and 3 used opioid antagonists.

Summary of opioid effects on sleep

Despite the inherent methodological limitations discussed above, the studies provide useful information about the effects of opioids on sleep. There are four basic phases of opioid dependence and withdrawal: drug induction phase, drug maintenance phase, acute abstinence phase and protracted abstinence phase.³⁸ Sleep architecture changes are different for each of the 4 phases. In general, during the induction phase, the use of morphine-like opioids significantly disrupts sleep with reduced REM sleep and SWS and increased wakefulness and arousals from sleep. TST and SE are usually reduced while percentage stage 2 sleep and REM sleep latency are often increased. During the maintenance phase of μ-opioid use, the decreases in SWS and REM sleep tend to normal as do the increases of wakefulness, arousal and REM sleep latency. Vocalization during REM sleep, significant delta burst and increased daytime sleepiness may commonly appear in this phase. Limited evidence is available regarding sleep during acute withdrawal from chronic opioid use.³⁸ Changes in sleep from withdrawal of short-term opioid administration³⁹ may be different to the changes seen in withdrawal from chronic opioid use. Significant insomnia is the major complaint during chronic opioid withdrawal, accompanied by frequent arousals and decreased REM sleep. During the protracted abstinence phase, TST significantly increases with rebound of SWS and REM sleep. After chronic methadone use, the rebound of SWS and REM sleep usually occurs between 13 and 22 weeks following withdrawal of the opioid.^{40 and 41}

Chronic opioid use is associated with symptoms of fatigue and excessive daytime sleepiness.^{12 and 14} The abnormal sleep architecture discussed above can affect daytime functioning in its own right. However, it is difficult to know how much the abnormal sleep architecture noted in these studies impacts on daytime function and excess daytime sleepiness.

Within the opioid class, morphine and methadone have comparable effects on sleep and are half as potent as heroin with regard to EEG measures.⁴² The difference between morphine and methadone on sleep is that chronic morphine use gives measures of persistent sleep architecture disturbances which are not found with chronic methadone use.^{40, 41 and 43} Further studies employing larger subject numbers and improved methodology are necessary to gain a clearer and more comprehensive understanding of opioid effects on sleep and to explore the long-term affects of sleep architecture changes on the subjects’ daytime function.

Respiration during sleep with acute opioid use

There are only two human studies assessing respiration during sleep with acute μ–opioid use. Robinson et al. assessed awake pharyngeal resistance, HCVR, HVR and respiration during sleep in 12 healthy adult humans after ingestion of 2 and 4 mg of oral hydromorphone.⁴⁴ Awake pharyngeal resistance, HCVR and breathing during sleep did not change significantly following either dose of the drug, although there is a trend toward increased apneas (more than doubled) and decreased hypopneas with the 4 mg dose. Awake HVR was significantly reduced after 4 mg of the drug.⁴⁴ Similarly, Shaw et al. measured breathing during sleep on 7 healthy adults after injection of morphine (0.1 mg/kg) and did not find an increase in sleep-disordered breathing compared to either baseline or placebo use.⁴⁵ Further studies with larger sample size are needed to test the effects of acute opioid use on respiration during sleep.

Respiration during sleep with chronic opioid use

Few studies have investigated respiration during sleep in subjects using opioids long term.^{13, 14, 15 and 46} The studies include two that assessed stable MMT subjects;^{13 and 14} one assessed 3 subjects using chronic time release opioid analgesics;¹⁵ and one assessed subjects with restless legs syndrome.⁴⁶ The stable MMT subject studies were the only studies that matched patients and normal subjects for age, sex and BMI.^{13 and 14} CSA was noted in 20 of 60 subjects in the MMT cohort and no CSA was noted in the normal subjects.^{13 and 14}

In the largest cohort study assessing respiration during sleep in subjects using opioids chronically, CSA was found in 30% of 50 stable MMT patients while obstructive sleep-disordered breathing was similar in the MMT cohort and normal subjects.¹⁴ The CSA in the MMT patients is more prominent in NREM sleep than in REM sleep and did not cause increased arousals compared to normal control subjects.¹⁴ The CSA described in stable MMT patients is of periodic and non-periodic type.^{13 and 14} During sleep, MMT patients have only mildly reduced arterial oxygen saturation and mildly increased transcutaneous arterial carbon dioxide tension.¹⁴

CSA, periodic breathing and Biot’s breathing pattern (i.e. “ataxic breathing” with unpredictable irregular pattern) was reported in 3 females using opioids chronically for pain relief.¹⁵ This report lacks data regarding a clear definition of “ataxic breathing” and whether the irregular breathing was or was not related to arousals or transitional sleep.¹⁵ This breathing pattern appears to be similar to sub-criteria CSA or the non periodic breathing CSA we describe in the stable MMT patients14 *D. Wang, H. Teichtahl, O.H. Drummer, C. Goodman, G. Cherry and D. Cunnington et al., Central sleep apnea in stable methadone maintenance treatment patients, Opioids have been suggested to interfere with pontine and medullary respiratory centres that regulate respiratory rhytmicity based on various cats studies.²⁷ To date there is however no evidence regarding the prevalence and possible mechanisms of the ataxic/Biot’s breathing pattern during human sleep in chronic opioid use.

Seven patients with restless legs syndrome were studied with PSG before and after long-term opioid monotherapy over an average of 7 years.⁴⁶ Two of the seven patients developed sleep apnoea with respiratory disturbance index of 10 and 15 and a third patient developed worsening of pre-existing sleep apnoea. The type of sleep apnoea found in the 3 patients was not reported.⁴⁶ It therefore appears that further studies with larger sample size and improved methodology are needed to elucidate if the CSA noted in stable MMT patients also exists in the patients using opioids chronically for pain relief and restless legs syndrome.

The outcome of the CSA observed in these groups of patients is unknown. For example, we do not know if these patients with CSA have higher morbidity or mortality than those patients using long-term opioids but without CSA. We also do not know whether the CSA noted in these patients contributes to daytime dysfunction, though it is clear that stable MMT patients are more depressed and sleepier during the day, and have poorer general health than normal subjects.^{14 and 47} What we do know is that CSA is not the sole cause of excess daytime sleepiness in the MMT patients.¹⁴

Potential mechanisms for CSA with chronic opioid use

Though the human studies showing CSA with chronic opioid use are of interest, only 2 have assessed potential mechanisms related to this finding.^{14 and 16} One of the major problems with using human subjects for investigating the pathogenesis of CSA in these populations is that chronic opioid use is usually associated with a number of other medical and psychiatric conditions.⁴⁷ Therefore, these subjects often use concomitant therapy such as benzodiazapines and antidepressants, and many have a history of cigarette abuse.⁴⁷ These confounders make it difficult to reach conclusions regarding pathogenetic mechanisms for CSA without testing large numbers of subjects and this can be difficult in these patient populations. We therefore suggest that future research be targeted at further developing animal models to better assess the mechanisms involved in CSA with chronic opioid use. However, even with the above caveats, the data obtained from our previous studies can give direction for further animal and human research and we will in detail discuss some of the information we have obtained in a cohort of stable MMT patients.¹⁴ These MMT patients were on stable doses of methadone and had been in the treatment program for a minimum of 2 months.

The CSA noted in the MMT patients appears to be different to the Cheyne–Stokes respiration seen in congestive heart failure patients.¹⁴ For example, the CSA of MMT patients shown in Fig. 2 are not of the crescendo–decrescendo type and have much shorter cycle time than the Cheyne–Stokes respiration of congestive heart failure.^{14 and 48} In addition these MMT patients had normal cardiac function.⁴⁹ The CSA in the MMT patients is not of the idiopathic type as these subjects lacked the typical characteristics of idiopathic CSA, such as male preponderance and significant arousals during sleep.^{14 and 50} Hypercapnia alone does not seem to explain the CSA in these stable MMT patients as their lung function tests were only mildly abnormal and their awake arterial CO₂ tension was marginally raised in only 10 of the 50 patients.⁴⁸

We currently believe that no simple cause and effect relationship can explain CSA with chronic opioid use. An important clue is that methadone blood concentration is the best predicting variable for CSA in stable MMT patients.¹⁴ Another important lead is that stable MMT patients have blunted central chemosensitivity but elevated peripheral chemosensitivity.¹⁶ We therefore believe that the pathogenesis for CSA in this group is most likely multifactorial in nature and related to a variable interplay of abnormalities of central controller function and central and peripheral chemoreceptor sensitivity. μ-Opioids are well known central respiratory depressants.⁵ The significant association between CSA and methadone blood concentration suggests that depressed central controller plays a critical role in the genesis of CSA.¹⁴ Structural brain damage has been reported to occur secondary to cerebrovascular accidents associated with prior illicit drug use.⁵¹ This brain damage particularly if it occurs in the midbrain or brainstem would lead to central respiratory controller dysfunction in these MMT patients. Functional and structural MRI studies are required in this group of patients to assess this hypothesis.

As shown in Fig. 1, stable MMT patients have significantly reduced HCVR but increased HVR, which may suggest blunted central chemosensitivity but elevated peripheral chemosensitivity.¹⁶ An imbalance of central and peripheral chemosensitivity has been suggested to pose a greater risk for periodic breathing.⁵² When carotid chemoreceptor stimulation becomes the dominant sensory input to the respiratory controller relative to the input of the medullary chemoreceptors, the breathing pattern tends to become instable.⁵² The combination of antidepressant and methadone use may further reduce the already blunted HCVR¹⁶ and lead to an increased risk of CSA.¹⁴ We have shown that of the stable MMT patients with CSA, 57% of those receiving both antidepressant and methadone had central apnoea index >10.¹⁴ These patients had significantly reduced central chemosensitivity compared to the patients taking methadone alone.¹⁶ This mechanism is therefore similar to that of hypercapnic-type CSA.⁵⁰ Acute opioids use can significantly reduce HVR, however, long-term application of opioids may lead to recurrent episodic hypoxia which may continuously stimulate peripheral chemosensitivity and lead to an increased HVR.^{14 and 28} It has been reported that exposing subjects to very mild and short-term hypoxia can cause an increase in HVR.⁵³ High peripheral chemosensitivity itself is a predisposing factor for sleep-disordered breathing⁵⁴ and has been shown to occur in high altitude periodic breathing⁵⁵ and in CSA of congestive heart failure.⁴⁸

The above mechanisms may contribute to the CSA seen in chronic opioid use. Each mechanism may occur in isolation or in variable combinations with other mechanisms.

Opioid use and SIDS

The SIDS is acknowledged as a major cause of death in infancy.⁵⁶ In Australia in the late 1990s’, SIDS killed approximately one in every 1200 infants. Neonatal life of infants born to substance abusing mothers or born to those using opioids chronically is similar to that of chronic opioid use followed by a natural opioid abstinence period. Following birth there is an acute withdrawal of supply of exogenous opioids through placental circulation while endogenous opioids production is low. This may cause functional impairment in the CNS and altered sleep patterns.⁵⁷ In pregnant MMT patients, foetal breathing movements and the response to carbon dioxide are significantly less than in normal subjects, and are further decreased after receiving methadone.⁵⁸ Infants born to substance-abusing mothers have been shown to have an impaired repertoire of protective responses to hypoxia and hypercapnia during sleep.⁵⁹ They have higher prevalence of periodic breathing during sleep and a 5–10 times increased risk of SIDS compared to normal infants.^{17, 18 and 59} In a population-based study, more than 1.2 million infants born in New York City between 1979 and 1989 were investigated and infants born to mothers in MMT were found to have 3.6 times increased chance of having SIDS compared to infants born to mothers not using methadone.⁶⁰

Practice points

• There is increasing acute and chronic use of illicit and prescribed opioids in Western societies.

• Sleep architecture is abnormal with opioid use and the abnormalities of sleep architecture are different across the four basic phases of opioid dependence and withdrawal.

• CSA including periodic and non-periodic breathing pattern have been reported with chronic opioid use and 30% of stable MMT patients have CSA. The potential impacts on patient outcomes of these findings are unknown.

• The mechanisms producing CSA with chronic opioid use probably involve changes in central and peripheral ventilatory control mechanisms.

• Infants born to substance abusing mothers have a higher prevalence of periodic breathing during sleep than normal infants and a 5–10 times increased risk of SIDS compared to infants born to non-substance abusing mothers.

Research agenda

• Assess the prevalence of sleep-disordered breathing in patients using opioids long-term.

• Animal and human studies are required to explore the pathogenesis of sleep-disordered breathing noted with chronic opioid use.

• Assess the short and long-term effects of sleep architecture changes and sleep-disordered breathing with chronic opioid use and investigate strategies to prevent the complications.

• Data is required regarding the acute and chronic interactions of opioids, antidepressants and benzodiazapines on sleep architecture and respiration during sleep.

• Animal and human studies with improved methodology are needed to assess the effects of acute opioid use on respiration during sleep.

• Data is required for patients with OSA undergoing surgery to assess the effects of opioid anaesthesia and of opioid analgesia on post-operative respiration both awake and during sleep.

• Develop clinical guidelines as to when patients using opioids should be investigated for sleep disorders including sleep-disordered breathing.

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Challenges in Using Opioids to Treat Pain in Persons With Substance Use Disorders

Pain and substance abuse co-occur frequently, and each can make the other more difficult to treat. A knowledge of pain and its interrelationships with addiction enhances the addiction specialist’s efficacy with many patients, both in the substance abuse setting and in collaboration with pain specialists. This article discusses the neurobiology and clinical presentation of pain and its synergies with substance use disorders, presents methodical approaches to the evaluation and treatment of pain that co-occurs with substance use disorders, and provides practical guidelines for the use of opioids to treat pain in individuals with histories of addiction. The authors consider that every pain complaint deserves careful investigation and every patient in pain has a right to effective treatment.

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Challenges