The Pharmacologic Management of Insomnia in Patients with HIV

Abstract

Insomnia is common in human immunodeficiency virus (HIV) seropositive populations. Some studies have estimated as many as 70% of HIV patients experience insomnia at some point during their illness. Insomnia has been linked to reduced quality of life as well as treatment non-adherence in these patients. However, there has been very limited research on the treatment of insomnia in this setting. Lacking treatment trials, we carried out a review of the available literature relevant to the pharmacologic treatment of insomnia in HIV seropositive individuals in order to provide guidance for the clinical management of this complex population.

A systematic MEDLINE search was performed using as search terms each of the FDA approved or commonly prescribed insomnia medications and “insomnia and HIV”. In addition, we reviewed the published literature on HIV therapies and common comorbid conditions and their interactions with insomnia therapies.

We found 4 primary factors affecting the pharmacotherapy of insomnia in individuals with HIV: (1) medications used to treat HIV; (2) antibiotics used to treat opportunistic infections; (3) the HIV infection itself; and (4) conditions frequently associated with HIV infection. The means by which these factors affect the expected risk-benefit profile of insomnia therapies is discussed, and recommendations are made for choosing medications in patients encountered in clinical practice.

Citation:

Omonuwa TS; Goforth HW; Preud’homme X; Krystal AD. The pharmacologic management of insomnia in patients with HIV. J Clin Sleep Med 2009;5(3):251–262.

I. INTRODUCTION

Insomnia is defined as persistent difficulty falling asleep, staying asleep, or non-restorative sleep which is associated with impaired daytime function.¹ Insomnia is common in the general population, with a prevalence estimated at 10% to 40%,² while the prevalence of insomnia in HIV positive individuals has been reported to be decidedly higher. In one study of HIV seropositive individuals in an outpatient setting, 73% had complaints of insomnia.³ It is tempting to assume that HIV associated insomnia is due to the stress of a highly stigmatized and potentially life-threatening physical illness, but this view is contradicted somewhat by a study of asymptomatic HIV positive men which showed that even prior to experiencing HIV/AIDS symptoms, there were more shifts to stage 1, increased awakenings, and lower sleep efficiency.⁴ This implies that infection with HIV may directly lead to changes in sleep.

The sleep changes that occur in HIV infection have been quantified in several studies employing polysomnography; however, the data are conflicting. There are reports of an increase in slow wave sleep that occurs primarily during later sleep cycles, but this finding has failed to be replicated in other studies.^5,6 Similarly, increased sleep latency, a reduction in the percentage of stage 2 sleep, and an increase in the number of nocturnal awakenings have been reported but have not been confirmed by subsequent studies.^4,7 Consequently, while it is accepted that sleep disruption in the context of HIV disease is common, the exact nature of this disruption remains unclear.⁸

The pathophysiology of insomnia in HIV is equally unclear. It is agreed that insomnia becomes a ubiquitous complaint in the latter stages of HIV infection,^9,10 which might suggest that HIV itself affects biological sleep centers. However, other potential compounding factors associated with HIV along the course of illness include medication effects, opportunistic infections, HIV associated dementia, and chronic bereavement (enduring depressed mood) due to cumulative loss of function.^2,11,12

Bearing in mind that some antiretroviral medications may impair sleep continuity,^11,13 which might lead some patients to stop treatment; adequate treatment of insomnia may lead to improvement in adherence to medications. One study of nonadherence in HIV patients showed that 10% of nonadherent subjects reported insomnia as a cause,¹⁴ although no association between insomnia and nonadherence was seen in subsequent studies.²

In spite of the potential links between insomnia, quality of life, and potential impact upon antiretroviral adherence, there have been no controlled treatment studies of insomnia in HIV seropositive populations. The only studies carried out to date have been uncontrolled and evaluated behavioral interventions including acupuncture and caffeine reduction.

One study addressed the efficacy of individualized acupuncture in 21 patients, and was able to demonstrate improvement in all patients over 10 sessions.¹⁵ Another treatment study examined caffeine reduction among people with HIV and showed a 35% improvement in the quality of sleep with caffeine reduction, but patients continued to have subjective sleep complaints.¹⁶ It is remarkable that there has yet to be a study of the treatment of insomnia in HIV patients with medication therapy, since medication management is by far the most common intervention used to treat insomnia in clinical practice.²

It is the goal of this article to review the literature related to the pharmacotherapy of insomnia in patients with HIV. The absence of controlled trials precludes carrying out a meta-analysis or even systematic review of treatment studies. Instead, we review the published literature related to the pathophysiology of HIV, the pharmacology of HIV therapies, and the pharmacology of medications used to treat insomnia in order to provide a synthesis of the available information to guide optimal pharmacologic treatment of insomnia in HIV seropositive individuals in clinical practice.

II. PRIMARY FACTORS AFFECTING PHARMACOTHERAPY OF INSOMNIA IN PATIENTS WITH HIV

We now review 4 primary factors affecting the pharmacotherapy of insomnia in individuals with HIV: (1) effects of medications used to treat HIV; (2) effects of antibiotics used to treat opportunistic infections; (3) effects of the HIV infection itself; and (4) effects of conditions frequently associated with HIV infection. Many of the effects of HIV on insomnia management are related to the hepatic clearance of medications. In this regard, there are 2 primary routes of metabolism: (1) cytochrome P450 enzymes and (2) glucuronidation using UDP-glucuronyl transferase, which makes drug metabolites more water soluble, thereby facilitating their clearance from the body.¹⁷

A. The Effects of Treatments for HIV on Insomnia Pharmacotherapy

The selection of antiretroviral medication in a HIV positive patient is a complex one that is out of the scope of this paper; however, it is important to have some understanding of therapy regimens as it relates to insomnia. HIV pharmacotherapy is accomplished using combinations of drugs from different drug classes—nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and cell membrane fusion inhibitors. According to guidelines developed by the US Department of Health and Human Services, treatment-naive patients should have either an NNRTI based regimen (usually efavirenz and a combination of 2 NRTIs) or a PI based regimen (often with a ritonavir co-formulation to increase the availability of the second PI).¹⁸

1. Non-nucleoside reverse transcriptase inhibitors (NNRTI). The NNRTI efavirenz, has the distinction of being the antiviral medication best documented to be associated with sleep disturbances. Nervous system adverse events including dizziness, insomnia, and fatigue are among the most common associated with this medication.¹⁹ Sleep effects of efavirenz include difficulty with sleep initiation and maintenance, as well as vivid nightmares; and the occurrence of these symptoms appears to correlate with efavirenz blood levels in affected individuals.¹¹ An ambulatory polysomnographic study in 18 HIV seropositive patients receiving efavirenz compared to 13 normal controls found that all patients on efavirenz had longer sleep latencies, reduced sleep efficiency, and reduced REM sleep; efavirenz serum levels were correlated positively with these changes in sleep.¹³

However, a majority of patients remain able to tolerate efavirenz well, and it remains a highly effective therapy against HIV even compared to protease inhibitor therapies.²⁰ One potential reason for these effects is that a subset of the population appears to develop increased blood levels of efavirenz due to hepatic cytochrome P450 2B6 polymorphisms. These individuals appear to develop neuropsychiatric adverse effects including fatigue and insomnia at high frequencies due to slowed metabolism and elimination of this agent.²¹ The majority of adverse effects associated with efavirenz resolve within 3 months, but intervention may be required to treat these side effects to encourage continued antiviral adherence in a population at high risk for self-discontinuation or partial non-adherence to HIV therapy.

2. Protease inhibitors. Of the protease inhibitors, ritonavir has been the most commonly reported to interact with insomnia therapy. Ritonavir is often used with other protease inhibitors to increase their availability. Co-formulation results in decreased pill burden, decreases the number of doses, fewer food and/or fluid restrictions, and a higher rate of viral suppression.²² When used in co-formulations, however, the dose of ritonavir is often not large enough to cause side effects, and any adverse effects observed are due to the protease inhibitor whose plasma concentration it is increasing.

The importance of ritonavir is related to its metabolism, which occurs primarily by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Ritonavir is a potent inhibitor of CYP3A and significantly increases the plasma concentrations of drugs dependent on CYP3A for metabolism—some drug concentrations may increase 77% to 20-fold in humans.²³ As a result, this medication may increase levels of a number of commonly administered insomnia agents, because their elimination is dependent on the CYP3A pathway (see Table 2).

Table 2.

Characteristics of Medications Used to Treat Insomnia in HIV Seropositive Patients

Agent	Tmax (h)	T1/2 (h)	Suggested Dose range	Metabolism	Abuse	First-Line Use	Relative Contraindications
Class: Benzodiazepines
Triazolam (Halcion)	1–3	2–5.5	0.125–0.25 mg	CYP3A4 Glucuronidation	++		Substance abuse, renal failure, hepatic failure, PIs, ketoconazole
Flurazepam (Dalmane)	0.5–1.5	40–250	15 mg	CYP2C19 CYP3A4	++		Substance abuse, hepatic failure, renal failure, PIs, ketoconazole
Quazepam (Doral)	2	20–120	7.5–15 mg	CYP3A4, CYP2C19	++		Substance abuse, hepatic failure, renal failure, PIs, ketoconazole
Temazepam (Restoril)	1–3	8–20	15–30 mg	Glucuronidation CYP3A4	++	+	Substance abuse, hepatic failure
Oxazepam (Serax)	3–6	2–5	10–30 mg	Glucuronidation	++	+	Substance abuse, hepatic failure
Lorazepam (Ativan)	1–3	12–15	0.5–1 mg	Glucuronidation	++	+	Substance abuse, hepatic failure
Alprazolam (Xanax)	1–3	12–14	0.5–1 mg	CYP3A4/5 CYP2C19	++		Substance abuse, PIs, hepatic failure, renal failure
Class: Non-Benzodiazepine Hypnotics
Zolpidem (Ambien)	1.7–2.5	2.0–5.5	5–20 mg	CYP3A4 CYP1A2 CYP2C9	+		Substance abuse, PIs, hepatic failure
Zaleplon (Sonata)	1.1	0.9–1.1	10 mg	Aldehyde Oxidase; CYP3A4	+		Substance abuse, hepatic failure
Eszopiclone (Lunesta)	1.3–1.6	6–7	2–4 mg	CYP3A1 CYP2E1	+		Substance abuse, hepatic failure, PIs, ketoconazole,
Class: Tricyclic Antidepressants
Doxepin (Sinequan)	1.5–4	10–50	10–25 mg	CYP3A4 CYP2C19 CYP2D6 CYP2C9 CYP1A2	−	+	Hepatic failure
Amitriptyline (Elavil)	2–5	10–100	10–50 mg	CYP3A4 CYP2C19 CYP2D6 CYP2C9	−		PIs, ketoconazole, hepatic failure
Class: Atypical Antidepressants
Mirtazapine (Remeron)	0.25–2	20–40	7.5–15 mg	CYP2D6 CYP1A2 CYP3A4	−	+	No absolute contraindications
Trazodone (Desyrel)	1–2	7–15	25–150 mg	CYP3A4 CYP2D6 CYP1A2	−		PIs, ketoconazole
Class: Antipsychotics
Olanzapine (Zyprexa)	5	30	2.5–5 mg	CYP1A2	−		PIs, hepatic failure
Quetiapine (Seroquel)	1	7	25–100 mg	CYP2D6CYP3A4	−		PIs, ketoconazole

Key: PI: Protease Inhibitor

Abuse Potential: − negligible; + mild; ++ mild-moderate

In addition to ritonavir, other protease inhibitors are known to affect 3A4. For example, amprenavir and fosamprenavir induce 3A4 while atazanavir, indinavir, nelfinavir, and saquinavir inhibit the enzyme.^24–27

3. Enfuvirtide. Enfuvirtide (T-20) is a fusion inhibitor that is the newest class of HIV related antiviral medication. It has a highly favorable profile with regard to drug-drug interactions, and there are no known significant medication interactions reported to date.²⁸

B. Antibiotics for Opportunistic Infections

With progression of HIV (and immunosuppression) it is important to offer prophylaxis against opportunistic infections. Common medications involved are ketoconazole/ fluconazole to prevent fungal infections and trimethoprim-sulfamethoxazole for Pneumocystis carinii prophylaxis. Ketoconazole and itraconazole are antifungals, which inhibit biosynthesis of triglycerides and phospholipids by fungi and alter the permeability of the cell wall by blocking fungal cytochrome P450. These agents have strong inhibitory effects on 3A4, 1A2, and 2C9 isozymes.^28,29 It can be expected that they will affect bioavailability of several drugs.^29–32

C. Aspects of HIV Infection That Might Affect Insomnia Pharmacotherapy

Treatment of insomnia in HIV seropositive individuals must take into account the possibility that progression of illness can lead to impaired renal function. It is estimated that 10% to 15% of people with HIV have chronic kidney disease. While kidney disease may be due to nephrotoxic medication, diabetes, hypertension, or heroin use; the renal impairment is often caused by a condition known as HIV-associated nephropathy (HIVAN). Risk factors for its development are older age, preexisting hypertension or diabetes, a prior AIDS-defining illness, injection drug use, and hepatitis C virus (HCV) co-infection.^33–35 Being African American and male are the strongest predictors for prediction of HIVAN.³⁶

Without treatment, progression to end-stage renal disease occurs in months. Treatment involves high-dose corticosteroids and optimization of antiretrovirals.³⁷ The impact of HIVAN on insomnia management is that it will greatly impair the elimination of medications which are renally excreted (see below). This will increase adverse effects and possible duration of effect; use of other medications is preferred.

D. Effects of Disorders Associated with HIV on Insomnia Pharmacotherapy

1. Hepatitis. HIV seropositivity is often accompanied by hepatitis B or C virus co-infection, which may be due in part to their similar modes of transmission. In the US, 15% to 30% of all HIV infected people are also coinfected with hepatitis C virus.³⁸ Among HIV infected drug users, the rate of hepatitis C coinfection has been estimated to be as high as 50% to 90%.³⁹

HIV seropositivity is often accompanied by hepatitis B or C virus co-infection, partly due to the similar modes of transmission.^40,41 Comorbid infection with HCV and HIV leads to higher rates of cirrhosis, which may lead to hepatic encephalopathy, a condition that often presents with sleep disturbance.⁴² In terms of insomnia pharmacotherapy, hepatic failure is important as it can lead to changes in metabolism of many drugs.^43–48

2. Alcohol/Substance abuse. The association between HIV and substance abuse may be direct (e.g., sharing of unclean needles) or indirect (e.g., acute intoxication often accompanied by disinhibition that leads to high-risk behavior). One study showed that 44% of new patients at a HIV clinic in Baltimore had an active substance abuse disorder.⁴⁹ In patients with history of abuse, use of agents with abuse potential such as benzodiazepines is relatively contraindicated because of the increased risk of abusing insomnia agents (compared to the general population).⁵⁰

III. ATTRIBUTES OF MEDICATIONS USED TO TREAT INSOMNIA AND THE IMPLICATIONS FOR USE IN PATIENTS WITH HIV

A large number of different prescription medications are used to treat insomnia. These medications can be broadly categorized as benzodiazepines, non-benzodiazepine hypnotics, antidepressants, and antipsychotics.⁵¹ In this section we discuss the major insomnia medications within each class and how their attributes are likely to affect their use in treating patients with HIV.

A. Benzodiazepines

The benzodiazepines are a group of compounds with related chemical structure that exert a therapeutic effect on sleep via binding to a site on the γ-aminobutyric acid (GABA) receptor complex and enhancing the inhibition that occurs when GABA—the predominant inhibitory neurotransmitter in the brain—binds to its receptor.⁵¹ All of these agents not only enhance sleep but also have anxiolytic, anticonvulsant, myorelaxant, amnestic, and psychomotor effects.⁵¹ Some benzodiazepines commonly used to treat insomnia are triazolam, temazepam, flurazepam, quazepam, lorazepam, oxazepam, and alprazolam ( Table 2).⁵¹

1. Triazolam: Triazolam is a relatively short-acting benzodiazepine (half-life 1.5–5 h) that is heavily dependent upon the P450 3A4 isozyme for metabolism ( Table 2). Triazolam’s t_max of approximately 3 h allows it to have a relatively rapid onset of action which is beneficial for sleep induction.⁵² However, triazolam also has been shown to improve total sleep time and improve the number of nocturnal awakenings in some studies as well. Because the half-life of triazolam is relatively shorter than other benzodiazepines, it is less likely to cause daytime sedation or impairment.^51,53 Because triazolam is primarily metabolized by the 3A4 isoenzyme, its pharmacokinetics are likely to be affected by protease inhibitor therapy (see section A1). As a result, the use of triazoloam may be problematic in many HIV seropositive patients.⁵⁴ Ritonavir has been found to reduce triazolam clearance to < 4% of non-inhibited values and increase the elimination half-life to 41 h from 3 h, thereby greatly increasing the likelihood of adverse effects with triazolam.⁵⁴ Similarly, triazolam is affected by ketoconazole, and coadministration should be avoided. Caution should be taken in patients with renal or hepatic impairment. Also, there is an abuse risk with triazolam and as such, it should be used with caution in patients with a history of substance abuse.

2. Flurazepam, Quazepam: Both of these agents are approved hypnotics that have been shown to decrease sleep latency and increase total sleep time.⁵⁵ Both agents are metabolized primarily through 3A4, and both have very long half-lives (80–100 h including active metabolites).⁵¹ Flurazepam and quazepam are both rapidly absorbed and reach peak concentration in approximately 2 h when taken orally. The long half-lives and active metabolites of these agents results in a significant likelihood that they will lead to daytime sleepiness and cognitive impairment, greatly limiting their use in the treatment of insomnia.⁵¹ Given this consideration and that the metabolism of this agent by cytochrome P450 3A4 is inhibited by protease inhibitors and ketoconazole, and would be greatly diminished in those with hepatitis, both of which would result in even longer duration of action, neither of these agents can be recommended for routine use in insomnia patients with HIV. Also, these agents are not recommended for routine use in patents with renal or hepatic failure or substance abuse.

3. Temazepam: This is an intermediate half-life benzodiazepine that is 98% protein bound, and exhibits a half-life of 8–14 hours, with peak absorption in 1–3 h ( Table 2). This agent is less lipid soluble than other benzodiazepines, so its onset of action is slower than the more lipophilic agents triazolam or alprazolam. The metabolism of temazepam involves both the CYP3A4 enzyme and glucuronidation (liver conjugation), with the latter playing a larger role.⁵⁶ In a randomized double-blind, placebo controlled trial of 7.5 mg, 15 mg, and 30 mg, all doses showed effects upon the latency to persistent sleep, but only the 30-mg dose showed effect upon decreasing the number of nighttime awakenings. Temazepam is preferred over many benzodiazepines for use in HIV seropositive patients, as there is no evidence that it would interact significantly with antiviral or antibiotic agents commonly used in this population, or be problematic in those with hepatitis.⁵⁷ As with the above medications, use with caution in hepatic impairment or substance abuse.

4. Oxazepam: Oxazepam is similar to temazepam in that it is an intermediate-acting benzodiazepine with a half-life of approximately 5 h. Its metabolism is by conjugation alone, so it should be low risk with regards to use in HIV seropositive patients on agents with significant P450 interaction. Data are scarce with regard to potential interactions with HIV medications, but at least one pharmacokinetic study of oxazepam dosed with the nucleoside reverse transcriptase inhibitor zidovudine demonstrated that the pharmacokinetics of neither zidovudine nor oxazepam were affected significantly when the other was used concurrently.⁵⁸ Oxazepam has been found to improve sleep in chronic primary insomnia patients and produced less daytime sleepiness and was better tolerated than flurazepam.^59–61 In summary, oxazepam is one of the safer benzodiazepines for use with HIV-positive individuals. Like temazepam, oxazepam should be used with caution in those with hepatic impairment or a substance abuse propensity.

5. Lorazepam: Lorazepam is also an intermediate-acting benzodiazepine that has a unique property in that it can be dosed orally, IM, or IV, which increases its utility in hospitalized patients. No placebo-controlled studies of the treatment of insomnia have been carried out with this agent. The effects of lorazepam have been compared with those of flurazepam in one study in insomnia patients.⁶⁴ Lorazepam improved both total sleep time and total wake time after sleep onset. Conversely, flurazepam only improved wake time. Side effects were identified only in the flurazepam group and consisted of grogginess and lethargy.⁶⁴

Lorazepam is primarily conjugated in the liver and its major metabolite is the glucuronide form. Blood concentrations of lorazepam peak in approximately 1–4 h.⁶⁵ The metabolism of this agent would not be expected to be affected significantly by medications used to treat HIV or hepatitis and is therefore an agent that may be useful for treating insomnia in many HIV seropositive patients. It is also, therefore, potentially useful for patients with moderate hepatic failure as the conjugation function of the liver tends to be preserved until later stages. It should be used with caution in patients who have a history of substance abuse.

6. Alprazolam: Alprazolam is an intermediate-acting highly lipophilic benzodiazepine that is similar in structure to triazolam; however, its metabolism is highly dependent upon 3A4. In at least one clinical study, ritonavir reduced alprazolam clearance to 41% of control values and markedly prolonged its elimination half-life (30 h versus 13 h).⁶⁶ In addition, benzodiazepine effects including sedation and performance impairment were also enhanced with protease inhibitor (specifically ritonavir) co-administration.⁶⁶ It is not recommended for use in patients with hepatic or renal impairment or substance abuse. Similar to triazolam, it is not a recommended agent for routine treatment of insomnia in patients with HIV illness.

B. Non-Benzodiazepine Hypnotics

Non-benzodiazepines are agents that are chemically unrelated to benzodiazepines but share with those agents that they improve sleep by binding to the GABA receptor complex and enhancing GABA-mediated inhibition (Krystal, in press).⁵¹ There is evidence in animal models that these agents may bind more selectively to GABA receptor complexes that are related to sleep effects and therefore may have less of the other effects of benzodiazepines such as anxiolysis, myorelaxation, dependence, and abuse.^50,51

1. Zolpidem: Zolpidem is approved for the treatment of sleep onset problems and zolpidem controlled-release is approved by the FDA for the treatment of sleep maintenance difficulties as well. Its half-life is 2.5–5 h, and it is metabolized in part via a P450 3A4 pathway which leads to a decreased rate of elimination in those with hepatic disease and a potential interaction with the protease inhibitors used to treat HIV ( Table 1).⁵⁴ One study examining the interactions between the protease inhibitor ritonavir and zolpidem noted that ritonavir reduced zolpidem clearance to 78% of control values; a slightly prolonged elimination half-life was also noted.⁵⁴ While this interaction does not preclude the use of zolpidem in an HIV seropositive population on protease inhibitor therapy, consideration should be given to using a lower dosage than usual, and the possibility of an increased risk of adverse effects should be kept in mind.

Table 1.

Sleep Complaints as a Result of Antiviral Medications

Antiviral Medication	Percentage and Types of Sleep Abnormalities in Clinical Trials	Metabolic Pathway Affected
Class: Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Abacavir	Abacavir + Lamivudine + Efavirenz 10% versus AZT/LAM/ Efavirenz 10%. Dreams, sleep disturbances	None reported
AZT	Not reported in clinical trials; insomnia reported post-marketing.	None reported
Didanosine	None reported.	None reported
Emtricitabine	Trial 303: EMT + ZDV/d4T + NNRTI/PI versus Lamivudine + ZDV/d4T + NNRTI/PI Abnormal dreams 2% vs 1%, Insomnia 7% vs 3% Trial 301A: EMT + didanosine + Efavirenz versus stavudine + didanosine + efavirenz Abn Dreams: 11% vs 19% Insomnia 16% vs. 21%	None reported
Lamivudine	Epivir + AZT 11% AZT 7%. Insomnia, sleep disturbances	None reported
Stavudine	Not reported in clinical trials; insomnia reported post-marketing.	None reported
Tenofovir	VIREAD + 3TC + EFV 5% d4T + 3TC + EFV 8% Insomnia	May inhibit 1A2
Zalcitabine	< 1% Insomnia	None reported
Class: Protease Inhibitors
Amprenavir	Sleep disorders not listed	Possibly induces 3A4
Atazanavir	ATA/LAM/AZT 3% AZT/LAM/Efavirenz 3% Insomnia	Inhibits a phase II glucuronidation enzyme UGT 1A1, inhibits 3A4
Darunavir	< 2% of pop, occ reported cases that were moderate severity and at least possibly related. Somnolence, nightmare	None reported
Fosamprenavir	Not reported	Its active metabolite induces 3A4
Indinavir	Not reported	Inhibits 3A4
Lopinavir/Ritonavir (Kaletra) + d4T and 3TC	2% insomnia	Induces Glucuronidation, In vitro inhibits 2D6 metabolism
Nelfinavir	< 2% insomnia post marketing	May induce 2C9, Inhibits 3A4c, 1A2, 2B6
Ritonavir	RIT 2% versus placebo 1.8% RIT Insomnia	After weeks of use, induces 3A4 metabolism. Also induces enzymes 1A2, 2C9, and 2C19 Potent inhibitor of 3A4, 2D6, 2C9, and 2C19. Moderate inhibitor of the 2B6 enzyme
Saquinavir	Saquinavir with ritonavir boost < 2% Excessive dreaming and insomnia	Inhibits 3A4
Tipranavir/Ritonavir	Tipranavir + Ritonavir + OBR 1.7% versus comparator PI/ ritonavir + OBR 3.7% Insomnia	See ritonavir
Class: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Delavirdine	DEL + ZDV 4.9% ZDV + 3TC 4.9% Insomnia	Potently inhibits 3A4. Also inhibits CYP2C9 and CYP2C19 in vitro
Efavirenz	Insomnia 7% vs 2 compared to indinavir regimen with ZDV and LAM Abnormal dreams 3% vs 0 Insomnia, abnormal dreams.	Induces 3A4 (induction is highest on day 10) Inhibits CYP3A4, 2C9, 2C19, Weak inhibitor of 2D6 and 1A2 in vitro
Enfuvirtide	None reported	None reported
Nevirapine	None reported	Induces 3A4
Class: Integrase Inhibitor
Raltegravir	None reported	None reported

Zolpidem is not recommended for patients with hepatic impairment but may be safe in those with renal impairment; however, caution must be used in those with a history of substance abuse.

2. Zaleplon: Zaleplon with a half-life of one hour and rapid absorption rate is approved by the FDA for the treatment of difficulties with sleep onset. Zaleplon is primarily metabolized by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase, although its short half-life decreases the likelihood of next-day effects even if elimination is slowed. Given the lack of interactions of zaleplon with medications used to treat HIV seropositive patients, it may be useful for the treatment of sleep onset difficulties in this population. In terms of hepatic function, zaleplon should be used at lower doses in moderate hepatic impairment and avoided in severe impairment. There are no contraindications to its use in renal impairment.⁶⁷

3. Eszopiclone: Eszopiclone is approved by the FDA for the treatment of sleep onset and maintenance difficulties. It is rapidly absorbed after oral administration and reaches peak serum concentrations in approximately 1 h with a half-life of approximately 6 h. Eszopiclone is metabolized primarily through the 3A4 pathway, so dosage adjustment is necessary in patients with hepatic disease as well as those receiving concomitant CYP 3A4 inhibitors such as ritonavir and ketoconazole.⁶⁸ No pharmacokinetic studies have been published regarding the effects of protease inhibitors on the metabolism of eszopiclone, however, caution and use of a lower than usual dosage (1 mg in adults) in those with hepatic disease and those receiving protease inhibitor therapy should be considered. It may be a safe option in patients with renal impairment but must be used with caution in substance abuse-prone individuals.

C. Antidepressants

While frequently used to treat insomnia, there are no antidepressants that are FDA approved for the treatment of insomnia.⁶⁹ In fact, their biggest limitation in terms of their use in treating insomnia is that there are hardly any data on their efficacy and safety in treating this condition. Here we review the antidepressants most commonly used to treat insomnia which include tricyclic antidepressants (doxepin, amitriptyline, and trimipramine), mirtazapine, and trazodone.⁶⁹ One important attribute of this class of agents which makes them desirable in HIV positive patients is that they have less abuse potential than the benzodiazepines.⁵⁰

1. Tricyclic Antidepressants: This class of agents exert their antidepressant effects by enhancing serotonergic and/or noradrenergic pathways by blocking reuptake.⁷⁰ These drugs also block histaminergic, cholinergic, serotonergic (5HT2) and α₁-adrenergic receptor sites, which results in their being associated with sedation, orthostasis, weight gain, dry mouth, constipation, and cardiac dysrhythmias.⁷⁰ The tricyclic antidepressants most frequently used to treat insomnia include doxepin and amitriptyline.⁶⁹

Doxepin: is a potent antagonist of histamine H₁ receptors used to treat insomnia at dosages below those typically used to treat major depression (< 75 mg) ( Table 2).⁷¹ At lower dosages (1–6 mg), this agent becomes a relatively selective H1 antagonist, resulting in greatly diminished side effects compared with higher dosages, while still retaining sleep enhancing effects (indicating a significant potential for the treatment of insomnia in this dosage range).⁷¹ It reaches maximum plasma concentration in 1.5–4 h after administration with a half-life of 10–50 h.⁵¹ It therefore has the potential to be beneficial for both sleep onset and maintenance. Its metabolism is stereoselective and involves CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP1A2.^72,73 A study by Haarter et al demonstrates a significant contribution of the polymorphic CYP2C19 to the N-demethylation of doxepin. CYP2C9 and CYP1A2 play a minor role and CYP3A4 does not contribute substantially.⁷⁴ Because there are multiple enzymes involved in its elimination, the presence of an antiretroviral agent that affects 1 or 2 of these enzymes would not be expected to significantly affect bioavailability. Considering this information, very low dose doxepin appears to be a good option for management of insomnia in an HIV population. While doxepin has the advantage of having a low abuse risk, it is not recommended for routine use in patients with hepatic failure at risk for encephalopathy because of its anticholinergic properties.

Amitriptyline: Another tricyclic antidepressant commonly used to treat insomnia is amitriptyline.⁶⁹ However, there have been no controlled studies of the treatment of insomnia with amitriptyline. This agent achieves maximum plasma concentration 2–5 h after administration and has a half life of 10–100 h ( Table 2).⁷⁵ Given the longer t_max, it is less likely to be effective in the treatment of sleep onset insomnia than other medications discussed. Unlike doxepin, there is no evidence that a dosage of this agent exists where it has therapeutic effects on insomnia without significant anticholinergic and antiadrenergic (block α₁) side effects. Pharmacokinetic studies of amitriptyline indicate that its metabolism is accomplished by CYP3A4, CYP2C19, CYP2D6 and CYP2C9.^76,77 While there are multiple P450 isozymes involved, 3A4 plays a large role in its elimination. This, in addition to its anticholinergic side effects means that it should be used with caution in patients at risk for encephalopathy or delirium. These facts, in addition to the unfavorable side effect profile makes amitriptyline a less compelling choice for routine use in patients with HIV.

2. Atypical Antidepressants Mirtazapine: Mirtazapine is an antidepressant that works as an antagonist of adrenergic α₂ receptors, 5-HT₂ and 5-HT₃ receptors, and also H1 receptors.⁷⁸ In terms of pharmacokinetics, peak plasma concentration is reached 1–3 h after dosing, making it potentially useful for patients with sleep onset difficulty; it has a half-life of 20 h, allowing it a significant place in the management of sleep maintenance insomnia ( Table 2).^52,79 Its sleep enhancing effect is believed to derive from H1 and 5HT2 antagonism.⁵¹ Potential side effects include sedation and weight gain.⁸⁰ The side effect of weight gain may be desirable among patients with HIV who can experience a loss of appetite or cachexia with the illness. Similarly, its 5-HT3 antagonism may be useful in HIV seropositive patients experiencing concurrent nausea or vomiting due to immune reconstitution syndrome with initiation of antiretroviral therapy.⁸¹ The metabolism of mirtazapine occurs in the liver using the cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4, with each of these contributing 25% to 45% to its net clearance. It has been shown that as mirtazapine concentrations increase, CYP3A4 contribution increases to about 70%, while CYP2D6, CYP2C8, CYP2C9, and CYP1A2 account for less than 15% each. However, it is unlikely that the absence of any one of these isoforms other than 3A4 would result in clinically significant changes to mirtazapine plasma concentration.⁸² It does appear to have low risk of abuse. In light of all these factors, mirtazapine appears to be reasonably safe in people with HIV; however, more studies are needed (especially in conjunction with ketoconazole which affects multiple cytochrome P450 enzymes).

Trazodone: Trazodone is a triazolopyridine antidepressant drug which inhibits serotonin reuptake, blocks 5HT2 receptors, and blocks α-adrenergic receptors.⁸³ This medication at dosages of 25–150 mg is the antidepressant most frequently used to treat insomnia, and, for many years, it has been the most frequently administered insomnia therapy despite the fact that it has been the subject of only one controlled trial in insomnia patients (in which it showed marginal evidence of utility).^69,84 The metabolism of trazodone involves the common CYP3A4 isoform of P450, but with trazodone, metabolic interactions are particularly problematic. This is because trazodone is metabolized to meta-chlorophenylpiperazine (mCPP) by 3A4. mCPP is a substance which acts as an agonist at 5-HT2 receptors, and is associated with sleep disruptive, anxiogenic, and dissociative effects.^85–89 Not surprisingly, co-administration with protease inhibitors, while protecting from side effects of mCPP, will cause increased sedation, fatigue, and performance impairment (due to decreased clearance of trazodone); in addition, it may lead to nausea, dizziness, hypotension, and syncope in some subjects.⁹⁰ Other studies have shown that there are also significant interactions with ketoconazole and indinavir. Similarly, protease inhibitors act also as CYP1A2 inducers, which would enhance the metabolization of trazodone and decrease its overall efficacy.⁹¹ Finally, because mCPP is metabolized by P450 2D6 co-ingestion of a potent 2D6 inhibiting agent such as fluoxetine will increase the risk of mCPP accumulation and toxicity.⁹² Trazodone is to be used with caution in patients with renal or hepatic impairment. For these reasons, despite the widespread use of trazodone as an insomnia treatment, it cannot be recommended for the routine treatment of insomnia in HIV seropositive patients.

D. Antipsychotics

While not FDA approved for insomnia, drugs in this class are often used to treat insomnia in practice, with olanzapine and quetiapine being the antipsychotic drugs most commonly used.⁶⁹ However, there has yet to be a placebo-controlled trial of the use of any of these agents in the treatment of this condition. In general, antipsychotics antagonize dopamine receptors, which may lead to extrapyramidal side effects such as parkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia.⁹³ It should be noted that patients with HIV have been noted to be especially sensitive to the extrapyramidal effects of these agents.⁹⁴ The atypical antipsychotics differ from the older agents in that they antagonize serotonin receptors along with dopamine receptors and are less likely to be associated with extrapyramidal side effects, although the risk for this in HIV infected patients remains substantial.⁹⁴ At the same time, these atypical antipsychotics can cause metabolic side effects like weight gain and hyperglycemia.⁹⁵ While this may be helpful in some circumstances for those HIV seropositive patients with anorexia, it is known that antiretroviral therapy (especially with protease inhibitors) commonly leads to lipodystrophy, hyperlipidemia, and insulin resistance.⁹⁶ With this in mind, antipsychotics should be used with caution to prevent further weight gain in patients with lipodystrophy or on protease inhibitors. On the other hand, antipsychotic agents with their low abuse potential may be more appropriate than benzodiazepines in those at increased risk for substance abuse.

Olanzapine: In addition to its anti-dopaminergic activity, olanzapine also has histamine H₁ blocking, anti-5-HT₂, anti-α₁ and anticholinergic effects.⁹⁷ These receptor effects mediate the observed side effects of this agent which include sedation, weight gain, orthostasis, dizziness, dry mouth, constipation, blurred vision, and urinary retention.^51,98 The sleep enhancing effects are believed to derive from the histamine H₁ blocking, 5-HT₂ antagonism, and α₁ antagonist effects.⁵¹ The time to maximum concentration is approximately 5 h, and the half-life is 20 h, which makes it unlikely to be effective for sleep onset insomnia, but likely to help sleep maintenance insomnia.⁵¹ It is metabolized by CYP1A2 and glucuronyl transferase, both of which are induced by HIV protease inhibitors.⁹⁹ At least one pharmacokinetic study in healthy volunteers indicates that larger doses of olanzapine may be necessary when it is co-administered with chronically administered ritonavir, given that ritonavir appeared to approximately double clearance of the drug (20 L/h to 43 L/h), and decrease half-life by approximately half (32 to 16 h).¹⁰⁰ As a result, higher dosages of olanzapine would likely be needed if used with chronic administration of ritonavir and other protease inhibitors. One study showed that olanzapine dose need not be adjusted for hepatic or renal impairment; however, monitoring of serum levels is recommended.¹⁰¹ It should be noted that the anticholinergic effects may worsen cognitive status in hepatic encephalopathy or other cases of delirium. Given the side effect profile of olanzapine and the relative risk of extrapyramidal side effects in HIV seropositive patients, olanzapine is not recommended as a first-line choice for the treatment of insomnia in HIV patients.

Quetiapine: Quetiapine mediates its effects via antagonism of histamine H₁, 5-HT₂, α₁ adrenergic, and dopamine D₂ receptors, and it is metabolized by CYP3A4 and CYP2D6. It reaches peak plasma levels in about 1.5 h and has a half-life of 7 h. Weigand’s study of 18 patients with primary insomnia demonstrated improved PSG parameters of total sleep time and sleep efficiency. However, there was no improvement in sleep onset latency. The majority of subjects had improvement of insomnia with 25 mg of quetiapine, which is a significantly lower dose than that used for antipsychotic effects (400–1200 mg/daily). At this very low dosage, quetiapine was well tolerated. There was no loss of efficacy in sleep parameters over a 6-week period, which makes quetiapine a promising option for long term management of insomnia.¹⁰² A study of single dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment, showed no differences in clearance when compared to controls.¹⁰³ Bearing in mind the previously mentioned propensity for quetiapine (and atypical antipsychotics) to cause hyperglycemia, weight gain and metabolic syndrome, it is not recommended as a first-line agent, but it is the most promising agent in this class of medications for use in insomnia in an HIV population based on pharmacokinetic considerations ( Table 2).

IV. SUMMARY AND SYNTHESIS

Treatment of insomnia occurring in the context of HIV should take into consideration, the clinical context of the particular patient. The primary contexts that should be considered include: (1) agents to use as routine first-line therapies; (2) protease inhibitor therapy; (3) NNRTI therapy; (4) antibiotic therapy; (5) liver failure; (6) renal failure; (7) substance abuse; and (8) patients with loss of appetite and weight.

A. Routine First-Line Therapies

For routine use, selected benzodiazepines such as temazepam, lorazepam, and oxazepam may be helpful. Of these, oxazepam may be most useful for sleep onset insomnia as it has a short half-life. The atypical benzodiazepine zaleplon may also be used routinely, although its use would be limited to those with sleep onset insomnia. Other good options for insomnia management include doxepin which can be used in very small doses for the treatment of insomnia (unlike its use in depression), and these low dosages improve substantially its side effect profile. Another option for routine use is mirtazapine which has a good safety and tolerability profile.

B. Protease Inhibitor Therapy

For patients who are being treated with protease inhibitors, appropriate insomnia medications would be low-dose antidepressants, such as doxepin and mirtazapine. Due to modified bioavailability in the presence of protease inhibitors, midazolam and triazolam use is contraindicated.

C. NNRTI Therapy.

For patients on NNRTI therapy (especially regimens containing efavirenz), insomnia may be a side effect of the medication. As these side effects tend to be time limited, the patient may see improved sleep over time. There is little data on what medication can be used to treat insomnia and sleep disturbances long term in patients on NNRTIs; however, in a case study, amitriptyline was able to alleviate sleep disturbances caused by efavirenz.¹⁰⁴ It is unclear how helpful amitriptyline would be in the general NNRTI- treated population.

D. Antibiotic Therapy

For patients on antifungals, coadministration of benzodiazepines metabolized by the liver cytochrome P450 isoenzymes (triazolam, midazolam, zolpidem, eszopiclone, etc.) is contraindicated. In addition, caution should be taken with use of doxepin, mirtazapine and trazodone. Instead, the patient may benefit more from some benzodiazepines based on their alternate route of metabolism: zaleplon, temazepam, lorazepam, or oxazepam.

E. Liver Failure

If a patient suffers from liver failure, benzodiazepines metabolized by the liver cytochrome P450 isoenzymes (triazolam, midazolam, zolpidem, eszopiclone, etc.), and tricyclic antidepressants should be used with caution. If the liver failure is mild to moderate, the patient may be treated with zaleplon, lorazepam, or temazepam at lower doses than usual. This group of patients may also benefit from low dose antipsychotics like quetiapine.

F. Renal Failure

In patients with renal failure, zolpidem, zaleplon, olanzapine, or quetiapine may be used. Of course, the other attributes of each of these drugs should be taken into consideration in deciding which to use. While most agents can be used in patients with renal insufficiency or failure, caution must be exercised and a reduction in the average starting dose by 25% to 50% is recommended. Agents can be titrated based upon clinical effect as tolerated.

G. Substance Abuse

For patients with a history of alcohol or substance abuse, it is recommended that benzodiazepines be avoided. A better choice would be antidepressants or antipsychotics such as doxepin, mirtazapine, or quetiapine.

H. Appetite and Weight Loss

For individuals with HIV who experience weight loss, agents which stimulate appetite may be beneficial. Agents with both 5HT2C antagonism and histamine antagonism are most likely to be effective in this regard.¹⁰⁵ Such agents include: atypical antipsychotics such an olanzapine or quetiapine, or tricyclic antidepressants such as amitriptyline or doxepin (in antidepressant dosages). Mirtazapine also has the advantage of being able to stimulate appetite and promote weight gain.

V. Directions for Future Research

There have been no placebo-controlled trials of the pharmacologic treatment of insomnia in HIV seropositive patients. Thus, the recommendations contained within this paper are based upon a review of the available literature which does not include reports of any placebo-controlled trials. Given the prevalence and impact of insomnia in this population, such trials are needed. Based on a review of the characteristics of the medications frequently used to treat insomnia, it will be most important to carry out placebo-controlled studies with agents such as doxepin, selected benzodiazepines, and mirtazapine to determine which are appropriate agents for routine first-line therapy. In addition, it would be helpful if these studies were conducted in the context of stable antiviral therapy, so that the alternating inhibition and induction of the P450 system caused by these agents would be less likely to change across the trial period. The antiviral medications should cover all the classes of drugs currently available to make it more generalizable to patients with HIV. Initially, it would be most useful to exclude those with hepatic or renal decline to control for an already complicated pharmacodynamics environment, and, following this, naturalistic studies involving patients in all these situations would be useful from a clinical standpoint.

DISCLOSURE STATEMENT

This was not an industry supported study. Dr. Krystal has received research support from Sanofi-Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sepracor, Takeda, Respironics, Neurogen, Evotec, Astellas, and Neuronetics and has consulted for Actelion, Arena, Astellas, Axiom, AstraZeneca, BMS, Cephalon, Eli Lilly, GlaxoSmithKline, Jazz, Johnson – Johnson, King, Merck, Neurocrine, Neurogen, Novartis, Organon, Pfizer, Respironics, Roche, Sanofi-Aventis, Sepracor, Somaxon, Takeda, Transcept, Research Triangle Institute, and Kingsdown, Inc. The other authors have indicated no financial conflicts of interest.