Sleep and Addiction

One of the major problems that I treat in people with significant substance use disorders is insomnia of all types.  I see people who have had insomnia since childhood.  A significant number have had insomnia and nightmares since childhood.  In that case the insomnia often precedes the development of any associated psychiatric diagnoses – it is a primary problem. In many cases, it is one of the reasons that people develop a substance use problem.  Alcohol, sedative hypnotics (often benzodiazepine type drugs), opioids, and cannabis are commonly taken for sleep and typically lead to many secondary problems.  Alcohol for example, will often lead to faster sleep onset, but as tolerance develops, the person will start to make up at 2 or 3 in the morning.  With increasing tolerance, a decision about taking more drinks at that time or toughing it out until the morning will need to be made. Some people can get to the point that they ingest large enough quantities of alcohol that they sleep the entire night and wake up with elevated blood alcohol levels.  Some do not realize the problem until they are arrested driving into work the next morning for intoxicated driving.

The available medications for treating insomnia in patients with addiction are limited.  We can currently treat a significant number of patients with sleep problems but there are still many that have very difficult to treat insomnia.

Medication	Probable Sleep Mechanism of Action
Trazodone	H-1 antagonist, NE antagonist, 5-HT2 antagonist
Doxepin	H-1 antagonist, NE antagonist, Ach antagonist
Mirtazapine	H-1 antagonist, 5-HT2 antagonist
Hydroxyzine	H-1 inverse agonist, Ach antagonist
Quetiapine	H-1 antagonist, NE antagonist, Ach antagonist, 5-HT2 antagonist, DA antagonist
Ramelteon	MT-1/MT-2 agonist  MT-1> MT-2
Melatonin	MT-1/MT-2 agonist  MT-1>MT-2
Prazosin	α1- adrenergic antagonist
Gabapentin	inhibition of the alpha 2-delta subunit of voltage-gated calcium channels
Benzodiazepines (detox only)	GABAA receptor agonist
Opioids (detox, MAT)	MOR agonist

 

The general strategy of using these medications is apparent from the purported mechanisms. For example, brain histamine (H) and acetylcholine (Ach) are alerting and arousing neurotransmitter systems so that antagonists/inverse agonists would be expected to decrease arousal and facilitate sleep.  Noradrenergic (NE) systems are wake promoting so NE antagonists would be expected to decrease this function.  The compounds in the above table work the best in addictive states when a person is abstinent from intoxicants and chronic use of intoxicants and after they have been detoxed.  Benzodiazepines and opioids are in the table for that purpose.  Although I have seen detox protocols that include many of the medications listed in the table as needed for insomnia and anxiety it is unlikely that they will work until detoxification has occurred.  In many cases, the expected duration of detox is much longer than anticipated and sleep problems are a prominent reason.    

That brings me to the primary focus of this post and that is a recent paper entitled “Drugs, Sleep, and the Addicted brain.” I generally don’t get too excited about research papers these days, but after reading this brief paper by Valentino and Volkow – I was fairly excited.  In this paper the authors main goal is to demonstrate how the biological substrates that regulate sleep interact with the reward system and how they can be direct targets for substance use. 

The first system they look at is the locus ceruleus (LC)-norepinephrine (NE) system that is involved in arousal. LC-NE neurons do not fire during REM sleep.  Activation of the LC results in firing of noradrenergic neurons that activate the cortex. Corticotropin-releasing factor (CRF) leads to LC activation and heightened arousal.  Endogenous opioids lead to damped excitation and decreased arousal.  Tolerance to exogenous opioids would lead to an expected inability to dampen the LC-NE system and increased activation and arousal during opioid withdrawal.

The serotonin (5-HT) dorsal raphe nuclei (DRN) system is also a system implicated in both sleep and arousal.   5-HT neurons are active during waking and do not fire during REM sleep. 

Histaminergic (H) neurons in the tuberomammillary nucleus (TMN) have an arousal function on cortical neurons.  They are active in the awake state.

Midbrain dopaminergic neurons (DA) in the ventral tegmental are (VTA) specifically those projecting to the nucleus accumbens (NAc) increase wakefulness upon activation but activation of the other major set of DA neurons in the substantia nigra has no effect.  This is a critical circuit in substance use because this system determines the value function of stimuli in the environment including addictive compounds and affects arousal.

Cannabinoids promote sleep, sleep onset, slow wave sleep, and sleep duration.  They decrease REM sleep.  CB1 agonists and antagonists respond in the expected manner.  The effects of CB1 agonism may be mediated by adenosine which increases in response to the stimulation of this pathway.  Caffeine is an adenosine antagonist and that may be the reason is promotes wakefulness.  Endocannabinoids also inhibit orexin neurons (arousal promoting) in the lateral hypothalamus and increase the activity of melanin neurons.  These combined effects of cannabinoids on the endogenous cannabinoid system explain the expected insomnia when these compounds are stopped for any reason.

The orexin system in the lateral hypothalamus and dorsal medical hypothalamus/perifornical area is activated during wakening and silent during sleep.  It is the system that is disrupted in narcolepsy.  It is also the system that coordinates the activity of the other arousal centers in the brain including the TMN-HA, LC-NE, DRN-5-HT, VTA-DA, and cholinergic neurons in the Nucleus Basalis of Meynert (NBM-Ach).  This relationship is depicted in the following graphic from the paper and detailed in reference 3.

Orexin A and Orexin B are wake  promoting neuropeptides the general structure of which is given below.  These peptides bind to Ox1R and Ox2R G-protein coupled receptors.  Orexin A has equal binding affinity to both receptor but Orexin B preferentially binds to the Ox2R receptor.  Detailed information is available from PubChem.

Human Orexin A

The orexin system may be critical not just in arousal but also in reward.  Patients with narcolepsy have orexin deficiency and generally do not overuse opioids and are less likely to overuse stimulants even though many have been prescribed very high doses.  Opioid users have increased orexin neurons in the lateral hypothalamus.  This increase in orexin signaling may lead to profound insomnia and the associated arousal state after prolonged exposure to opioids and makes this insomnia very difficult to treat.  Orexin can directly potentiate reward in some models.  Orexin is implicated in states where a high level of motivation to acquire the target substance is required or where there are external stimuli like stress, and specific cues for drug use that lead to increased motivational states.  The authors in reference 2 refer to orexin's ability to affect the approach toward a reinforcing stimulus or active withdrawal from an aversive stimulus as motivational activation.

Suvorexant is an interesting compound in that it antagonizes Orexin A and Orexin B wake-promoting neuropeptides and prevents them from binding to Ox1R and OXxR receptors decreasing wakefulness.  It is currently FDA approved as a treatment for insomnia, but the authors propose that it is a compound of interest in that it can potentially counter the arousal and reward potentiation associated with drug seeking states.  If that is the case it could be a useful treatment for both insomnia and the primary addictive disorders.

When I look at possible treatments for insomnia in addiction, a central question is whether or not they will potentially worsen the addictive state.  That is why there are no specific benzodiazepine related sleep compounds in the table at the top of this post.  The benzodiazepines listed there are all basically used on a short term basis for detox and then tapered and discontinued.  In the case of mu-opioid receptors (MOR), medication assisted treatment with both buprenorphine and methadone are possible on an ongoing basis. The package insert for suvorexant suggests possible problems in that subjects with recreational polydrug use rated their "liking" of the drug as being similar to zolpidem 15 and 30 mg doses.  Zolpidem is a standard sedative hypnotic that can be used to treat insomnia.  It definitely has abuse potential and in some cases patients can end up taking very high doses per day until they can be detoxified.  That is not reassuring in terms of safety for persons with substance use problems but I would not take it as proof that it cannot be safely used.  According to the DEA, suvorexant is currently a Schedule IV drug or low potential for abuse or dependence. Some articles on insomnia suggest that despite what appears to be a comprehensive mechanism, the short term efficacy of suvorexant is no greater than zolpidem but at a much greater cost.

I am currently looking at the medicinal chemistry and clinical trials literature to assist me decision making on orexin receptor antagonists and just how much of withdrawal related insomnia is due to orexins. The other important question is whether it will also decrease drug seeking states and withdrawal avoidance.   

George Dawson, MD, DFAPA

References:

All full text and all excellent

1: Valentino RJ, Volkow ND. Drugs, sleep, and the addicted brain. Neuropsychopharmacology. 2020;45(1):3–5. doi:10.1038/s41386-019-0465-x

2: James MH, Mahler SV, Moorman DE, Aston-Jones G. A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?. Curr Top Behav Neurosci. 2017;33:247–281. doi:10.1007/7854_2016_57

3: Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015. doi:10.1523/JNEUROSCI.18-23-09996.1998

Graphics Credit:

The brain graphic is from reference 1 and is used here without modification per the Creative Commons Attribution 4.0 License.

Disclaimer:

This post may change significantly over the next two weeks.  I had to put it up to see what it looks like and plan to elaborate the behavioral pharmacology of orexin and the pharmacology of suvorexant.