Novel Drug Combinations as Pharmacotherapies for Cocaine Use Disorder

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3 Novel Drug Combinations as Pharmacotherapies for Cocaine Use Disorder Craig R. Rush, PhD University Research Professor Behavioral Science [Professor]; Psychiatry [Professor and Vice Chair for Research; Psychology [Professor] University of Kentucky November 12, 2018

4 Acknowledgments Faculty Collaborators Wm. W. Stoops, PhD Joshua A. Lile, PhD Lon R. Hays, MD, MBA Abner O. Rayapati, MD Paul EA Glaser, MD, PhD Post-Docs and Grad Students Joseph L. Alcorn III, PhD Erika Pike, PhD Anna R. Reynolds, PhD Justin Strickland, MA LHBP Staff Frances P. Wagner, RN Bryan Hall, MA All the hard-working RAs

5 Acknowledgments l l l This work was funded by grants from the National Institute on Drug Abuse (NIDA): R01 DA (PI: Rush, CR) R01 DA (PI: Rush, CR) R01 DA (PI: Rush, CR) R56 DA (PI: Rush, CR) R01 DA (PI: Stoops, WW) R01 DA (PI: Lile, JA) This funding agency had no role in study design, data collection or analysis or preparation or submission of presentations/publications. Content is solely the responsibility of the authors and does not necessarily represent the official views of NIH.

6 Conflicts I have accepted consulting fees from Collegium Pharmaceuticals. I accept an honorarium annually from Elsevier Publishing for editorial services to Drug and Alcohol Dependence. I collaborate with Embera NeuroTherapeutics, Inc.

7 Introduction l Stimulant-use disorders in general, and cocaine-use disorder (CUD) in particular, are unrelenting public health concerns despite prevention and intervention efforts. l Prevalence of cocaine use and cocaine use disorder has been stable for the last five years (SAMHSA, 2017).

8 Introduction Prevalence of cocaine use and cocaine use disorder has been stable for the last five years (SAMHSA, 2017). The number of overdose deaths involving cocaine increased between 2010 and 2016 (NIDA, 2018; Warner et al., 2016). Only heroin and synthetic opioids showed a larger increase in overdose deaths during this time (i.e., 4-8 fold).

9 Overdose Deaths in USA National Institute on Drug Abuse (NIDA)(Accessed June 20, 2018)

10 Introduction l Cocaine overdose rates in Black men rival those of opioid overdose in White men (Shiels et el., 2017).

11 Overdose Rates Shiels et el. (2017)

12 Introduction Individuals that reported experiencing withdrawal symptoms following prescription opioid reduction and/or cessation had a significantly greater odds of also reporting current (i.e., past month) stimulant use. Center for Behavioral Health Statistics (2017)

13 Odds of Past Month Drug Use with Odds Opioid of Past Use and Month Withdrawal Drug Use with Opioid Use and Withdrawal Methamphetamine Cocaine Prescription Stimulants Tranquilizer/Benzodiazepines Marijuana Alcohol Center for Behavioral Health Statistics (2017)

15 Introduction Ellis, Kasper and Cicero (2018)

16 Introduction Ellis, Kasper and Cicero (2018)

17 Introduction l While behavioral therapies are effective for reducing cocaine use many patients are unable to achieve significant periods of abstinence suggesting other strategies like pharmacotherapy are needed. l An effective medication has not been identified for CUD even though it has been a priority for the National Institute on Drug Abuse for nearly 3 decades.

18 Introduction l The inability to identify an effective pharmacotherapy for cocaine use disorder suggests novel strategies are needed. l Evaluating medications effective for disorders that share behavioral and neurobiological substrates with substance use disorders could yield treatments for managing cocaine use disorder.

19 Obesity and Cocaine-Use Disorder l Obesity is a significant public health concern. l Approximately 35% of adult Americans are obese, while another 35% are overweight. l Because of the prevalence of obesity, the pharmaceutical industry is interested in developing novel compounds for weight management. l While typically considered distinct clinical entities, obesity and cocaine addiction share common behavioral, neurobiological and pharmacological substrates.

20 Behavioral, Neurobiological and Pharmacological Similarities Between Obesity and Cocaine-Use Disorder Behaviorally, both obesity and cocaine use disorder can be defined as increased saliency of one reinforcer (i.e., food or drug) over other reinforcers. Food and cocaine increase synaptic dopamine levels. Dopamine levels were measured via microdialysis in the nucleus accumbens of rats that self-administered food and cocaine (Hernandez and Hoebel, 1988). Bar pressing for food reward resulted in a nearly 40% increase in extracellular dopamine levels. Cocaine (20 µg) injections in to the nucleus accumbens resulted in a five-fold increase in extracellular dopamine levels.

21 Behavioral, Neurobiological and Pharmacological Similarities Between Obesity and Cocaine-Use Disorder l Obesity and cocaine-use disorders share a common neurobiological perturbation. l Comparable reductions in striatal D 2 dopamine receptor availability is seen in obese and cocaine-addicted individuals. l Obese patients (N=10) had significantly lower striatal D 2 dopamine receptor availability than controls (N=10) (i.e., Bmax/Kd: 2.47 and 2.99, respectively, p < 0.008) as determined by positron emission tomography (Wang et al., 2001). l There was a significant negative correlation between Body Mass Index (BMI) and striatal D 2 dopamine receptors availability in the obese patients. l A previously previous study showed a similar reduction in striatal D 2 dopamine receptors availability in cocaine-dependent patients relative to controls (Volkow et al., 1990, 1993).

22 Wang et al. (2001) Group average images of [C-11] raclopride (distribution volume image) and FDG (metabolic image) PET for obese individuals and controls at the level of the basal ganglia.

23 Wang et al. (2001) Correlation between dopamine receptor availability (Bmax/Kd) and BMI in obese individuals.

24 Volkow et al. (1993) 18 FN-methylspiroperidol images in a normal control and in a cocaine abuser tested 1 month and 4 months after last cocaine use. The images correspond to the four sequential planes where the basal ganglia are located. The color scale has been normalized to the injected dose. Notice the lower uptake of the tracer in the cocaine abuser when compared with the normal control. Notice the persistence of the decreased uptake even after 4 months of cocaine discontinuation.

25 Obesity and Cocaine-Use Disorder l l Based on these behavioral and neurobiological similarities, medications that reduce body weight might be effective for cocaine use disorder. Some have asked: Can anti-obesity drugs be repurposed to treat stimulant use disorder (Reiner and Bossert, 2018)? l Translational evidence suggest appetite suppressants (i.e., amphetamines) attenuate the reinforcing may be effective for cocaine use disorder.

support to support the efficacy theofefficacy a medication of a

26 Translational Research Translational Research To what extent do findings from these three domains of of research converge to support to support the efficacy theofefficacy a medication of a medication for methamphetamine for methamphetamine use disorders? use disorders?

27 Preclinical Experiments l Cocaine injections are delivered contingent on a response (e.g., lever press). l Non-human laboratory animals readily self-administer cocaine. l Because the reinforcing effects of cocaine are central to its abuse potential, an effective pharmacotherapy will necessarily modify drug self-administration.

28 Preclinical Experiments l l Preclinical laboratory experiments have assessed cocaine self-administration in animals maintained on several appetite suppressants. These studies have involved different species and different drug selfadministration arrangements.

29 Preclinical Experiments Wilson and Schuster (1973)(Continuous Reinforcement)

Preclinical Experiments Saline 0.032 Amphetamine 0.

30 Preclinical Experiments Saline Amphetamine 0.1 Amphetamine Negus and Mello (2003) (Second-Order Schedule)

31 Preclinical Experiments Negus and Mello (2003) (Cocaine [0.01 mg/injection)

32 Preclinical Experiments Negus and Mello (2003) (Cocaine [0.01 mg/injection)

33 Conclusions: Preclinical l Appetite suppressants (i.e., amphetamines and fenfluramine) attenuate the reinforcing effects of cocaine. l These findings are consistent with the notion that the neurobiological substrates of obesity and cocaine use disorder overlap.

34 Human Laboratory Studies l Only a few human laboratory experiments have tested the efficacy of appetite suppressants as putative pharmacotherapies for cocaine use disorder. l The available studies have used drug self-administration procedures as well as subject-rated drug-effect questionnaires.

35 General Procedures Placebo-controlled, double-blind, inpatient, human clinical pharmacology study. Subjects reside on an inpatient clinical science research unit for approximately four weeks. Followed for two weeks after discharge. Patients are paid for their participant. Carefully screened prior to enrollment. Met criteria for cocaine use disorder, self-reported recent use, provided a drug positive urine sample. Cocaine administered intranasally or intravenously under controlled medical conditions. IRB and FDA approved.

36 Human Laboratory Studies l We determined the initial efficacy and safety of d-amphetamine for cocaineuse disorder. l Seven (7) non treatment seeking, cocaine dependent participants completed the protocol. Rush et al. (2009)

37 Human Laboratory Studies Rush et al. (2009)

38 Human Laboratory Studies Rush et al. (2009)

39 Human Laboratory Studies l We further determined the initial efficacy and safety of d-amphetamine for cocaine-use disorder using a drug choice procedure. l Nine (9) non treatment seeking, cocaine dependent participants completed the protocol. Rush et al. (2010)

40 Human Laboratory Studies Rush et al. (2010)

41 Human Laboratory Studies l l We then determined the efficacy and safety of d-amphetamine for cocaine use disorder using a progressive ratio procedure and intravenous cocaine. Sixteen (16) non treatment seeking, cocaine dependent participants completed the protocol. Lile et al. (2018)

42 Human Laboratory Studies Lile et al. (2018)

43 Human Laboratory Studies Lile et al. (2018)

44 Human Laboratory Studies Lile et al. (2018)

45 Conclusions: Human Lab Studies l Cocaine can be safely administered to participants maintained on appetite suppressants like d-amphetamine. l l d-amphetamine, a potent appetite suppressant, attenuated the reinforcing effects of cocaine. The results of human laboratory studies further support the notion that the neurobiological and pharmacological substrates of obesity and cocaine use disorder overlap.

46 Clinical Trials l l Double blind, placebo-controlled, randomized trials are the gold standard of clinical research. Only through the conduct of placebo-controlled clinical trials can the efficacy of appetite suppressant for the management of cocaine use disorders be determined. l Moreover, only through the conduct of placebo-controlled clinical trials can the publichealth relevance of laboratory-based research be ascertained.

47 Grabowski et al. (2004)(d-Amphetamine) Clinical Trials Placebo 15/30 mg 30/60 mg

48 Clinical Trials Mooney et al. (2009)(Intent to Treat Analysis)

49 Conclusions l l l Preclinical experiments, human laboratory studies, and clinical trials suggest amphetamines, which are potent appetite suppressants, may be a viable strategy for managing cocaine use disorders. Cocaine can be administered safely to participants maintained on amphetamine, which is often a concern of clinicians and regulatory agencies (i.e., FDA). Clinicians may be reluctant to use amphetamines for cocaine use disorder because of their abuse potential.

50 Abuse Potential of d-amphetamine in Cocaine Abusers l To our knowledge, there are three published studies that determined they abuse potential in cocaine users. l Oral d-amphetamine is nearly devoid of positive subjective effects (Bolin et al., 2016; Comer et al., 2013; Reed et al., 2016) and reinforcing effects (Reed et al., 2016) of cocaine users.

51 Abuse Potential of Acute d-amphetamine in Cocaine Abusers Like Drug Comer et al. (2013)

52 Abuse Potential of d-amphetamine in Cocaine Abusers Bolin et al. (2016)

53 Maximum Rating (0-4) Abuse Potential of d-amphetamine in Cocaine Abusers Reed et al. (2016)

54 Conclusions l Cocaine can be administered safely to participants maintained on amphetamine. l l Oral amphetamine appears to have minimal abuse potential in cocaine-using participants. Nevertheless, more research is needed to identify novel appetite suppressants that attenuate the reinforcing effects of cocaine and reduce drug use.

55 Drug Combination Therapy l Mono-therapies including amphetamines and phentermine are effective for obesity, but typically produce only modest reductions in body weight (i.e., 5-10%) (Rothman, 2010). l l While these reductions are associated with decreases in complications associated with obesity (e.g., cardiovascular morbidity and mortality), greater weight reduction would likely result in further health benefits. The modest reductions observed with mono-therapies have led some to suggest that multiple medications may need to be administered in order to achieve larger reductions in body weight (Rothman, 2010).

56 Drug Combination Therapy l The overarching premise of this approach is that combining medications might maximize efficacy and minimize side effects. l Perhaps the best-known example of this approach was the phentermine-fenfluramine combination, although it was removed from the market due to serious adverse effects. l Consistent with the notion that the neurobiological substrates of obesity and cocaine addiction overlap, phentermine-fenfluramine combinations reduce body weight and attenuate the reinforcing effects of cocaine.

57 Drug Combination Therapy Glowa et al. (1997)

58 Drug Combinations l Medication combinations should: Target multiple neurotransmitter systems. Consist of constituent drugs that have some efficacy when tested alone. Minimize side effects by using lower doses of the constituent drugs, perhaps improving adherence to treatment. Produce additive or synergistic reductions in drug consumption. Lee and Leggio (2014); Stoops and Rush (2014)

59 Bupropion-Naltrexone (Contrave ) Combinations l l l l l A bupropion-naltrexone combination is approved for the treatment for obesity Bupropion is a dopamine reuptake inhibitor. Naltrexone is an opioid antagonist When tested separately as mono-therapies for obesity, bupropion and naltrexone are modestly effective. Combining bupropion and naltrexone results in significant weight loss.

60 Bupropion-Naltrexone (Contrave ) Combinations Greenway et al. (2009)(Bupropion [400 mg/day])

61 l Bupropion-Naltrexone (Contrave ) Combinations We recently determined the efficacy of bupropion-naltrexone combinations for cocaine-use disorder. l Thirty one (31) non treatment seeking, cocaine use disorder participants completed the protocol.

62 Rush et al. (2018) Bupropion-Naltrexone (Contrave ) Combinations

63 Rush et al. (2018) Bupropion-Naltrexone (Contrave ) Combinations

64 Rush et al. (2018) Bupropion-Naltrexone (Contrave ) Combinations

65 Peak Systolic Blood Pressure (±SEM) Bupropion-Naltrexone (Contrave ) Combinations Placebo 100 mg Bupropion 200 mg Bupropion 400 mg Bupropion 135 Naltrexone (0 mg) 135 Naltrexone (50 mg) Cocaine Dose (mg) Cocaine Dose (mg) Rush et al. (2018)

66 Future: Bupropion-Naltrexone Combinations l A grant that proposed to conduct a Phase II clinical to determine the efficacy of a bupropion-naltrexone combination for cocaine use disorder received a favorable priority score, but was not funded.

67 Topiramate-Phentermine (Qysmia ) Combinations l A topiramate-phentermine combination (Qysmia ) is approved for obesity ( l Combining low doses of topiramate and phentermine is at least as effective as higher doses of the constituent drugs alone.

68 Topiramate-Phentermine (Qysmia ) Combinations Astrup and Toubro (2004)(Topiramate Alone)

69 Topiramate-Phentermine (Qysmia ) Combinations 8.3% Kang et al. (2010)(Phentermine DCR Alone [30 mg])

70 Topiramate-Phentermine (Qysmia ) Combinations Allison et al. (2011)

71 l Topiramate-Phentermine (Qysmia ) Combinations We determined the initial efficacy of topiramate-phentermine combinations for cocaine-use disorder. l Twenty eight (28) non treatment seeking, cocaine use disorder participants completed the protocol.

72 Topiramate-Phentermine (Qysmia ) Combinations Rush et al. (2016)

73 Rush et al. (2018) Topiramate-Phentermine (Qysmia ) Combinations

74 Rush et al. (2018) Topiramate-Phentermine (Qysmia ) Combinations

75 Rush et al. (2018) Topiramate-Phentermine (Qysmia ) Combinations

76 Rush et al. (2018) Topiramate-Phentermine (Qysmia ) Combinations

77 Future: Topiramate-Phentermine Combinations l A grant that proposed to conduct a Phase II clinical to determine the efficacy of a topiramatephentermine combination for cocaine use disorder received a very favorable priority score, but was not funded.

78 Duloxetine-Methylphenidate Combinations l l Methylphenidate reduces food intake in adolescent and adults (Danilovich et al., 2014; Goldfield et al. 2007; Leddy et al., 2004; Vansickel et al., 2007). Duloxetine also reduces food intake in adults (Guerdjikova et al., 2012).

79 Vansickel et al. (2007) Duloxetine-Methylphenidate Combinations

80 Duloxetine-Methylphenidate Combinations Cocaine use disorder is also characterized by perturbations in DA, NE and 5HT systems. Duloxetine, an antidepressant, has high affinity for the 5HT and NE transporters (k i = 0.8 and 7.5 nm, respectively), but lower affinity for the DA transporter (k i = 240 nm). Methylphenidate has high affinity for the DA transporter (k i = 34 nm), but lower affinity for the 5HT and NE (k i 10,000 and 339 nm, respectively). Combining duloxetine and methylphenidate will functionally produce a triple monoamine-uptake inhibitor with high affinity for the DA, 5HT and NE transporters.

81 Duloxetine-Methylphenidate Combinations

82 Rush et al. (2018) Duloxetine-Methylphenidate Combinations

83 General Conclusions l Topiramate-phentermine combinations clearly reduce cocaine self-administration. l Duloxetine-methylphendiate combinations also appear to reduce cocaine self-administration. l Both of these combination warrant further investigation as putative pharmacotherapies for cocaine-use disorder. l Federal funding agencies, however, are not enthusiastic about these combinations because of concerns regarding a regulatory pathway to approval.

84 References l l References are available upon request. crush2@ .uky.edu

85 Mixed Reviews! That s very interesting Craig, but the dog needs to be walked! Your research is way cool G- Daddy!

86 I like the walk idea!

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