Pharmacy considerations in tobacco cessation for patients suffering from posttraumatic stress disorder

INTRODUCTION

Post-traumatic stress disorder (PTSD) is an anxiety disorder often coupled with comorbid conditions including substance abuse disorder, chronic pain, depression, and tobacco use disorder. Multiple studies have associated PTSD with variable and high rates of smoking documented in different populations. The literature reports a smoking prevalence of greater than 40% in individuals with PTSD. A causal relationship has even been suggested based on temporal associations and comparisons of smoking rates in veteran twins with and without PTSD.¹

Patients with PTSD are at an increased risk for cardiovascular disease and cancer, which may conceivably be linked to their increased incidence of smoking. In a sample of veteran patients undergoing cardiac catheterization, patients with psychiatric conditions and tobacco use disorders were five times more likely to have substantial coronary artery stenosis, compared with veterans without these conditions.² A link between psychiatric pathology and worsened cardiac disease outcomes, aside from increased tobacco use, has been confirmed.³ It is crucial to address modifiable risk factors, such as tobacco use, in psychiatric patients.

Smoking cessation has proven difficult for all individuals. Those with PTSD face unique challenges due to stronger addictive features and higher quantities of cigarettes smoked. PTSD patients may quickly be discouraged from cessation attempts due to more significant cravings, habit withdrawal, and negative affect compared to smokers without PTSD following overnight abstinence.⁴ A cohort of 445 Vietnam combat veterans with and without PTSD did not demonstrate higher rates of smoking in the PTSD group. However, those with PTSD were more likely to be heavy smokers (25 or more cigarettes per day) compared to combat veterans without PTSD (48% vs. 28%).⁵ A patient's relative risk for both cardiovascular disease and/or lung cancer increases in proportion to the number of cigarettes smoked per day and number of smoking years.⁶ Although total abstinence is always the goal of therapy, a reduction in smoking could be an appropriate preliminary goal for patients.

Specific PTSD symptoms, such as “emotional numbing”, are correlated with an increase in self-reported cigarettes used per day. Severity of PTSD symptoms as a whole, as indicated by the Clinician Administered PTSD scale (CAPS) scores, was not correlated with the degree of smoking. Symptoms of emotional numbing were also positively associated with a greater number of cigarettes per day, higher Fagerström Test for Nicotine Dependence (FTND) scores, and a shorter time to first cigarette.⁶ This finding is consistent with data showing that Iraq and Afghanistan Veterans with PTSD and symptoms of emotional numbing are more likely to smoke than those without these symptoms.⁷

NEUROBIOLOGY

The investigations into the neurobiology of nicotine addiction have released an extraordinary amount of data explaining why patients continue to smoke cigarettes. Theories regarding addiction continue to emerge. Nicotine is present on ubiquitous nicotinic acetylcholine receptors (nAChRs) leading to a release of various neurotransmitters causing pleasure, arousal, mood modulation, appetite suppression, decrease in anxiety/tension, and cognitive enhancement.⁸

In addition to the release of neurotransmitters, nicotine stimulates the release of adrenocorticotropic hormone (ACTH) by activating the hypothalamic-pituitary-adrenal (HPA) axis. The result is a lower concentration of corticotrophin-releasing factor (CRF) in smokers versus non-smokers.¹ PTSD has shown elevated levels of CRF. A 2007 study searching for an investigative target for treating nicotine withdrawal identified an interesting finding. Triggered withdrawal in nicotine-dependent rats produced a hyper-release of CRF in the amygdala. The resulting activation of CRF receptors implicates a connection between anxiety, nicotine withdrawal, and the desire to self-administer nicotine. The overstimulation of the CRF – CRF1 system and the resultant decrease in dopamine in the amygdala is characterized as a stressor. Antagonism may offset this aversive feeling of withdrawal, decreasing the need for nicotine self-administration.⁹

The reward and adverse effects of nicotine are integrated within the ventral tegmental area (VTA), which is located in the midbrain. Drug-induced reward and its motivational effects are brought on by a surge of dopamine (DA) from the VTA and into the shell of the nearby nucleus accumbens (mesolimbic DA pathway). Augmentation of this neurotransmitter is accomplished by nearby cortical, sub-cortical and brainstem structures with associated glutaminergic and cholinergic influences. Gammaminobutyric acid (GABA) and dopaminergic neuronal activity predominate in the VTA. Early acute nicotine administration affects GABA neurons the most. Chronic use of nicotine, however, desensitizes the receptors on these neurons by continued glutaminergic influence. In time, this excitatory signal mutes and bypasses the inhibiting power of GABA, and activates DA neurons downstream.⁸¹⁰ Equally important are the complex neuronal links between the tegmental pedunculopontine nucleus (TPP), the adjacent laterodorsal tegmentum (LDT), which are both in the brainstem, and the VTA. The TPP has been implicated in research to be a vital mediator of the nicotine reward signal while the LDT and its glutaminergic input essentially regulates the tonal and propulsive activity of dopamine from the VTA.¹¹¹²

When activated by an agonist, the nAChR channel opens. Through chronic use, the receptor can also become desensitized. Left unoccupied over time, it becomes very sensitive in the presence of nicotine. This may explain the pleasurable feeling that patients describe first thing in the morning with that first cigarette of the day. Unoccupied and desensitized, nAChRs reflect a relative decrease in dopamine activity in the dopamine reward pathway. The smoker, now feeling the decrease in pleasure he or she has been accustomed to, is experiencing the aversive effects of nicotine- craving and withdrawal.⁸ The aversive character of nicotine has also been found to be a function of nicotine concentration in the VTA, peripheral nAChr activation, acute versus chronic administration, and the degree of loss in dopamine release in the mesolimbic pathway.¹⁰ Over time, he/she is conditioned to respond by smoking in order to achieve that sudden increase in dopamine. Emotionally, the smoker understands the importance of saturating these receptors in order to keep them desensitized. It has been observed that an up-regulation of receptors takes place after the nAChRs become desensitized and tolerance begins to develop. The positive effects of nicotine can also drive the need to smoke in a variety of situations. One can modulate mood and arousal to take emotional control of their daily life (and all of the stressors that go with it). Concentration, reaction time, and skill performance tends to improve. These positive effects may all be erased by nicotine withdrawal and the ensuing risk of expressing mood disturbances increases.⁸

Genetically, we have clues to why some smokers may struggle with smoking cessation while others do not. Each nicotinic ACh receptor has 5 sub-units. Of the 12 currently possible sub-units known to exist, all are either α or β units. Identified are α2 − α10 and β2 − β4. The receptors' pentameric structure can be heteromeric, meaning that they have a combination of α and β subunits, or they may be homomeric, with either α or β subunits exclusive to the form of the receptor. Different subunits of nACh receptors express variable responses to nicotine. In the human brain, α4β2, α3β4, and α7 nicotinic receptors predominate. Mediating nicotine dependence is thought to be dictated by α4β2. Murine deletion of the β2 sub-unit has been observed to express less dopamine release and a decrease in self-stimulation when activated by nicotine. Normal expected behavioral responses to nicotine reappear when the β2 sub-unit is added back in. A mutation in the α4 sub-unit in mice made them hypersensitive to nicotine. Research using rats showed effects on the cardiovascular system via the α3β4 receptor and homomeric α7 sub-units. The α7 sub-unit itself has its own list of attributes: 1) the regulation of glutamate release in the CNS, and 2) enhancement of auditory regulation, learning and memory in laboratory rats.^8.10

VARIATIONS IN TREATMENT RESPONSE

In addition to psychosocial and neurobiological factors used to explain a higher smoking prevalence, there are other hypotheses to account for higher smoking rates in psychiatric patients. These suggest lower appreciation for medical consequences of smoking in psychiatric care providers, who are more likely to smoke themselves compared to providers in other specialties. Preference may be given to mental health treatment or focus may be placed on cessation of other abused substances, including alcohol. Though smoking cessation may not be given priority, individuals treated for alcohol dependence were more likely to die from the consequences of tobacco rather than alcohol.¹³ Clinicians may underestimate the motivation to quit in psychiatric patients. In a sample of 205 psychiatric outpatients with various diagnoses, 43% were contemplating and 28% were preparing for smoking cessation. These rates, however, are similar to the general smoking population.¹⁵

Integrating tobacco cessation treatment into mental healthcare has proven to be more efficacious for achieving prolonged abstinence in veteran patients, compared to treatment in separate cessation clinics. The quit rate with integrated therapy was 8.9% with abstinence bioverified by carbon monoxide and cotinine levels and 15.5% with self reported abstinence, compared to 4.5% bioverified and 7% self reported abstinence in the control group. All quit rates were lower than those found in groups unaffected by mental health conditions. An important study finding was that psychiatric symptoms were not increased in either group of patients, as they attempted or achieved abstinence from smoking. On the contrary, CAPS scores (measuring PTSD symptoms) improved for both patient groups. One or more cessation medications was provided to a similar, high percentage of patients in the study groups (84% and 79.3%). Integrated care patients had statistically significantly greater days of any tobacco cessation medication. A greater number of integrated care patients used bupropion monotherapy or combination bupropion and NRT. More predictive of effective treatment than medication use was the number of counseling sessions received. This evidence reinforces the role for medications as an adjunct to vital counseling sessions as a mainstay of therapy.¹³

TOBACCO DEPENDENCE TREATMENT

All current approved pharmacotherapies for tobacco dependence are considered first line. Pharmacotherapy options are certainly encouraged, although no specifics were defined to guide the choices in patients that have PTSD.¹⁶ When selecting a pharmacologic agent, one has to rule out precautions and consider the patient's previous experiences and preferences.

It seems counterintuitive to treat dependence of a substance by giving the substance. In the case of nicotine and nicotine replacement products, one is doing just that. Pure nicotine in nicotine replacement therapy (NRT) is absorbed slower into the vascular system than nicotine in cigarette smoke. Since the most commonly used NRT products, transdermal and oral, are available over the counter, it is important to counsel patients on the safety of nicotine use because any misuse can lead to illness. Pooled RCT data comparing NRT versus placebo indicates a higher risk of palpitations and chest pain (OR=2.06), skin irritation from the patch (OR= 2.80), nausea and vomiting (OR=1.67), and GI issues (OR=1.54). The most frequently occurring side effects were hiccoughs (OR= 7.68) and coughing (OR= 2.89), which was associated with the use of the oral products.¹⁷

The sympathomimetic drive of nicotine yields an initial increase in blood pressure, pulse, and inotropic characteristics. Insulin sensitivity wanes and endothelial dysfunction becomes a threat in nicotine's presence for smokers with coronary artery disease. No further cardiovascular effects, however, was observed in a nicotine medication dose-response curve and no additional increase in pulse or catecholamine release was expressed. This was further supported by a clinical trial in smokers with cardiovascular disease indicating no increased risk of CV events with nicotine patch use versus placebo.¹⁸

Precautions involve a recent myocardial infarction, significant cardiovascular changes, arrhythmias, unstable angina, and hypersensitivity to the patch. All NRT products are pregnancy category “D” with the exception of nicotine gum (C).¹⁸

Transdermal nicotine replacement probably achieves the highest compliance because it is replaced once a day at the patient's convenience. If the patient complains of insomnia or vivid dreams while using the patch, adjusting the dose by applying the patch first thing in the morning and removing it before bedtime is an acceptable method for reducing the amount of nicotine the patient receives in 24 hours.¹⁹ If a high level of nicotine needs to be matched and replaced, however, the patch is appropriate, and one may need to add nicotine gum or lozenge to accommodate extremely heavy smokers. Some patients may experience local skin reactions, but the inflammation can be treated with over-the-counter hydrocortisone cream.¹⁶ The daily replacement patch should be applied in a different location anywhere above the waist, including the back and arms- and please, not over the heart. For men with an ample supply of body hair, a little shaving may be necessary to assist with adhesion.

The replacement of nicotine is effective in reducing the symptoms of nicotine withdrawal during smoking cessation. Unfortunately for the patch, positive reinforcement responds to how fast the nicotine is absorbed. The nicotine patch delivers nicotine to the body slowly and gradually and therefore may not be effective in preventing withdrawal.¹⁸ This rate-controlled formulation gives a constant delivery of nicotine regardless of skin permeability.

The transdermal delivery system is not designed to be cut and nicotine levels may become too elevated if the patch is compromised. Removal of the patch is also required prior to an MRI to avoid burns to the skin. The nicotine retained in the patches after removal is poisonous to pets and children. The patch must be properly disposed of once it is used by folding it in half with the sticky sides touching, and placing it back in its original pouch for disposal.¹⁸²⁰

Nicotine gum, lozenge, oral inhaler, and nasal spray are options listed in ascending order of increasing rates of nicotine absorption. The two latter choices are prescription products. These short-acting NRTs help the smoker deal with the urges to smoke, on an as needed basis, by theoretically keeping the nicotine receptors desensitized enough to make the cigarettes less attractive to use.18.²¹ All of these medications allow flexible dosing, but some are easier to use than others. There is no superior NRT product based on effectiveness, and the selection depends on patient adherence to a particular product and the degree of craving expressed.²¹ It has been shown that transdermal nicotine was effective in a long term trial for a period of 24 weeks. Efficacy, however, disappeared after treatment was stopped.²⁸

Nicotine gum, unfortunately, is probably the most misused nicotine replacement product on the market. Although OTC directions make the use of the product easy to understand, patients still need considerable counseling in order to use the nicotine gum effectively.

SUPPLEMENTAL NICOTINE IN SMOKING CESSATION IN PATIENTS WITH PTSD

There are two ongoing studies to assess the relationship between PTSD symptoms, tobacco withdrawal, mood, and relapse with interventions of transdermal nicotine, bupropion, placebo and Cognitive Behavioral Therapy. Results from both randomized clinical smoking cessation trials should be available sometime in 2013.³²³³

DRUG INTERACTIONS

There are potentially significant interactions that may occur when pharmacotherapy for tobacco cessation is combined with treatments for PTSD. The polycyclic aromatic hydrocarbons present in cigarette smoke induces the Cytochrome P450 1A2 isoenzyme and may decrease the concentrations of various medications (used in the treatment of PTSD) that are substrates of CYP 1A2 including amitriptyline, imipramine, fluvoxamine, and propranolol.³⁴³⁵ Patients older than 60 years of age or suffering from cirrhosis or hepatitis are known to have decreased Phase I metabolic activity, making it less likely that cigarette smoke would affect enzyme efficiency.²⁶

Treatment options for PTSD that are substrates of CYP450 2D6 include fluoxetine, paroxetine, venlafaxine, fluvoxamine, propranolol, clonidine, amitriptyline, and imipramine.³⁴³⁵ Bupropion used in smoking cessation is a potent inhibitor of Cytochrome P450 2D6 and may increase the concentrations of these medications. All of these medications (except venlafaxine and clonidine) are metabolized by multiple CYP enzymes, and their concentrations are less likely to be affected due to alternate metabolic pathways.²⁶³⁴

The only two FDA approved medications for the treatment of PTSD are Paroxetine and Sertraline.³⁵ Sertraline has been shown to increase levels of bupropion (metabolized by CYP450 2B6) in mice.²⁴

VARENICLINE-CONTROVERSIES IN SAFETY

Scientists developed a new molecular entity for smoking cessation, varenicline, that is a partial agonist at the α4β2 receptor. The property of agonism would replace some of the pleasure of nicotine by a partial release of dopamine, and the ability to antagonize the presence of nicotine at the same time was unique for a smoking cessation drug. Varenicline was approved by the FDA in May of 2006. This recognition for use was accomplished with the exclusion of patients with psychiatric illnesses in the registration trials. By the end of 2007, 988 serious injuries were reported to the FDA involving this drug. Because this accounted for more serious adverse events than any other drug in the United States for this time period, the Institute for Safe Medication Practices produced a pilot program to identify the drug risks by monitoring the FDA adverse effects reports on a quarterly basis.²⁷ Their final report highlighted cases of suicidal gestures and thoughts, possible psychosis, and aggression numbering in the hundreds. Less common were reports of suicide, homicidal ideation, hallucinations and paranoia. Other adverse effects reported were visual disturbances, heart rhythm irregularities, abnormal muscle spasms and movements, skin reactions, and loss of glycemic control.²⁷ Reported accidental injuries due to unconsciousness, mental confusion, dizziness, and abnormal muscle movements along with the other adverse effects listed above lead to the recommendation that varenicline use be prohibited in air traffic controllers, pilots, and commercial vehicle operators in the United States.²⁷³⁰

In January of 2012, a systematic review and meta-analysis of randomized controlled trials involving the long-term efficacy and safety of varenicline was published.²⁹ The primary objective focused in on long term (> 6 month) efficacy of varenicline versus placebo or nicotine transdermal systems. But equally important was the update of evidence regarding the psychiatric side effects of varenicline in lieu of the FDA special report on the potential psychiatric risks mentioned earlier. The authors reported there were no significant increases in psychiatric side effects observed for varenicline versus placebo. Included in the meta-analysis, a population based study of a large cohort of 89,660 participants reported no clear evidence of varenicline being associated with an increased risk of fatal or non-fatal self harm and no evidence of an increased risk of depression or suicidal thoughts. Conclusions from the authors, however, express the need for a more definitive study. Also, considering the limitations observed in the meta-analysis, they suggest that people with mental illness be cautiously treated for tobacco dependence using varenicline.²⁹

Prudence is paramount in the treatment guidelines defined by the Department of Veteran Affairs. The VA guidelines state that the exclusion criteria for the use of varenicline include:

• Patients with a history of suicidal, homicidal, or assaultive behavior within the previous 12 months.

• Patients with current, persistent suicidal or homicidal ideation or an active plan or intent to harm self or others.

• Patients with an untreated or unstable mental disorder such as, but not limited to, psychotic disorder, bipolar disorder, major depressive disorder, and PTSD.

The inclusion criteria state that the patient must have clinical psychiatric stability and be monitored every 28 days with documentation of no adverse effects in order to continue therapy. VA criteria for use dictates that varenicline should not be combined with other smoking cessation pharmacotherapies.³¹

THE USE OF VARENICLINE IN SMOKING CESSATION IN PATIENTS WITH PTSD

Varenicline, with all of its safety issues and reported neuropsychiatric side effects, is still a first line agent in some guidelines in the treatment of tobacco dependence.¹⁶²¹ This is not the case when considering varenicline for smoking cessation in PTSD patients. A 2010 retrospective cohort conducted at a single VA Medical Center concluded that patients with PTSD had more mental health encounters during a 4 to 12 week treatment period taking varenicline, compared with defined baseline periods (6 months before and 3 months follow-up). The study was a small chart review, but did post a nearly 30% increase in documented mental health encounter contacts with a psychiatrist, psychologist, or mental health nurse practitioner during therapy with varenicline in patients diagnosed with PTSD. Because there were no difference in the number of mental health encounters during the pre- and post-varenicline baseline periods, the authors' conclusion suggested a destabilizing effect caused by varenicline.²

CONCLUSION

Awareness of the significant extent of PTSD patients in need of smoking cessation treatment is vital to improving the overall physical and perhaps mental health of these patients. To date, however, little concrete evidence is available to guide the treatment of tobacco cessation specifically for smokers with PTSD. Pharmacists in various settings can play an important role in helping patients and providers select appropriate therapy.

Nicotine medications in over-the-counter and prescription formulations have shown ease of convenience and a variety of options for a patient to select from. Special considerations have been given to drug interactions and psychiatric medications when using bupropion. The monitoring of mood changes and other psychiatric symptoms has proven necessary to ensure the safe use of varenicline. Selection of the products necessary for treatment is based on the assessment of benefit and risk with a given drug regimen in the treatment of PTSD.

Smoking cessation therapy integrated into the mental healthcare setting with counseling added to drug treatments has shown good outcomes compared with previous models. Proven integrated therapy in PTSD patients and the knowledge of drug actions and interactions can direct therapy in safe and effective management of tobacco cessation. Counseling, support, and follow-up can best be expedited by pharmacists and their armamentarium of tobacco cessation products. Knowing this, we recommend that the intensity of combination therapy and counseling equal the intensity of nicotine withdrawal symptoms. This can be determined with the use of the Fagerström test for nicotine withdrawal. Along with weekly phone or email communications with the patient, the use of these strategies can help the pharmacist establish a therapeutic alliance valuable in the treatment of this difficult addiction co-morbid with posttraumatic stress disorder.