- Email: [email protected]
Utilizing Buprenorphine in the Emergency Department after Overdose
16. Ayanga, D. et al. (2016) Update on pharmacotherapy for treatment of opioid use disorder. Exp. Opin. Pharmacother. 17, 2307–2318 17. Skolnick, P. and Volkow, N.D. (2016) Re-energizing the development of pain therapeutics in light of the opioid epidemic. Neuron 92, 294–297 18. Chan, H.C.S. et al. (2017) Designing safer analgesics via m-opioid receptor pathways. Trends Pharmacol. Sci. 38, 1016–1037 19. Schmid, C.L. et al. (2017) Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175 20. Truong, P.M. et al. (2017) Modulation of opioid receptor affinity and efficacy via N-substitution of 9b-hydroxy-5-(3hydroxyphenyl)morphan: synthesis and computer simulation study. Bioorg. Med. Chem. 25, 2406–2422
Series: Opioid Crisis
Science & Society
Utilizing Buprenorphine in the Emergency Department after Overdose Sade E. Johns ,1,* Mary Bowman,1 and F. Gerard Moeller1 The United States is currently in the midst of an opioid epidemic. Barriers to treatment in the emergency department can lead to missed opportunities for helping prevent overdose and relapse in individuals with opioid use disorder. The administration of buprenorphine in the emergency department can potentially lead to better treatment outcomes for these individuals. The Opioid Epidemic The United States is in the midst of an opioid misuse epidemic. There has been a steady and dramatic increase in opioid-related overdose deaths in the United States over the past 10 years, with more than 42 000 overdose deaths in 2016i. A 2016 report estimated that 998
about 11.8 million people aged 12 years or older had misused opioids in the previous year [1]. Both prescription opioid use and heroin use have also increased in the United States. In 2016, an estimated 626 000 people had a heroin use disorder and an estimated 2.1 million people had a prescription drug use disorder [1]. This rise in prescription opioid misuse and heroin misuse has led to an increase in opioid-related deaths and overdose. This increase has also led to a strain in emergency departments (EDs). From July 2016 to September 2017, visits for opioid-related overdoses rose 30% in the United Statesii. Recent data show that many opioid overdose victims will have a repeat overdose event after ED admittance without outpatient treatment [2]. Current treatment referral procedures from the ED are insufficient, with only 37% of ED referrals leading to treatment engagement at 30 days post the initial encounter with a simple referral to outpatient treatment [3]. As recently reported in the New York Timesiii, there is a growing interest in the use of buprenorphine, a partial m-opioid agonist, in the ED setting for the treatment of opioid addiction. It is our opinion that the use of buprenorphine in the ED after opioid overdose may lead to better treatment retention and lower risk of repeat overdose.
Buprenorphine and Buprenorphine/Naloxone Buprenorphine is a partial m-opioid agonist that is approved by the FDA for the treatment of opioid use disorder (OUD). It has been shown to reduce withdrawal during opioid abstinence and reduce the risk of overdose [4]. As a partial agonist at the m-opioid receptor, buprenorphine has lower risk of overdose than other full agonists, such as methadone or oxycodone [4]. The approval of buprenorphine by the FDA for office-based
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12
treatment; the passage of the Drug Abuse Treatment Act of 2000 (DATA 2000) that allows qualified physicians to prescribe buprenorphineiv; and support from the National Institute on Drug Abuse allowed for buprenorphine to be used to treat OUDs in an office-based setting. By contrast, methadone can only be dispensed in a federally regulated methadone clinic. This, in turn, expanded the access to treatment for opioid dependence [5]. However, while buprenorphine has a lower abuse potential than other opioids, there are concerns about its misuse and diversion [6]. Because of these concerns, buprenorphine has now been made available in several formulations including the addition of a buprenorphine/naloxone combination. In 2003, a combination of buprenorphine with the opioid antagonist naloxone (Suboxone1) was marketed for the treatment of opioid dependence. This combination tablet was created to help reduce the misuse and abuse of buprenorphine through intravenous use and was to be administered sublingually (applied under the tongue). The addition of naloxone deters misuse because if taken in another route such as via injection, naloxone can precipitate withdrawal symptoms in opioid-dependent individuals. Furthermore, a film form of buprenorphine/naloxone was licensed in the United States in 2010. The film also deters misuse as its form makes it least likely to be taken in an unprescribed route such as intravenously or through snorting [7]. The FDA has recently approved the buprenorphine/naloxone combination film Cassipa1 for treatment of opioid dependencev. Both Cassipa and Suboxone have FDA approval for name brand as well as generic formsv,vi.
Treating Patients with OUD in the ED While EDs across the United States provide daily high-quality acute care to those
in need, they are increasingly becoming overcrowded from being frequently used as an entry point for people seeking care for non-urgent and/or chronic medical conditions. This is particularly true for vulnerable populations with limited resources, including many individuals with OUD. Situated on the front lines of the national opioid crisis, EDs treat opioid overdoses and the complications of OUD and addiction daily. These complications can include conditions such as skin infections from injection of opioids and withdrawal symptoms such as nausea, vomiting, and diarrhea. Despite being involved with opioid abuse patients frequently, there are many challenges in an emergency care setting that providers face to truly help those who struggle with addiction. Currently, the primary option available to the patients who present to the ED and request assistance with opioid abuse is a referral to outpatient addiction treatment services [3]. Given the rapid pace of a typical ED, providers may not have time to provide opioid counseling, assist in helping patients with engaging in care in an inpatient or outpatient treatment center, or be able to customize resources to the patient’s specific needs related to his or her current substance use disordervii[6_TD$IF]. The transition of care from the ED to a substance abuse treatment center is a high-risk time for patients, and coordinated care is essential to limit the potential for opioid withdrawal and relapse. While there is considerable attention focused on the opioid epidemic itself, there has been less emphasis on establishing best practices for treatment of OUD in an ED setting or for transitioning patients with OUD from the ED to appropriate substance abuse services such as inpatient rehabilitation centers or outpatient medicationassisted therapy centers [67_TD$IF][8].
to initiate long-term treatment for OUD. A 2015 study by D’Onofrio et al. [3] showed that when patients in the ED were given buprenorphine in conjunction with a brief intervention and an outpatient referral, the number of patients who continued to engage in substance abuse treatment was significantly higher than for those who were only given a referral or had a brief intervention and a referral. In our opinion, initiating substance abuse treatment with medications such as buprenorphine in the ED setting, a fairly new concept, can help prevent future relapse.
Use of Buprenorphine in ED to Prevent Opioid Relapse
concerns that using buprenorphine in the ED will dramatically increase ED visits due to the lack of outpatient buprenorphine providers. In addition, apart from opioid misuse, treatment of comorbidities such as chronic pain and psychiatric illness also need evaluation and post-ED treatment in such patients. A resolution of these issues will require a more direct connection between ED and outpatient treatment for opioid addiction. Moreover, before using buprenorphine in patients with OUD in the ED setting, pertinent questions will need to be addressed. These questions include: what percentage of patients who survive opioid overdose are willing to initiate buprenorphine in the ED; what doses and formulations achieve the best follow-up treatment engagement; and what is the timeline needed for outpatient follow-up visits post opioid overdose? However, despite these barriers and remaining questions, we believe that ED-initiated buprenorphine treatment post opioid overdose provides a potential novel method to potentially break the cycle of repeat opioid overdose and death.
Before arrival in the ED after an opioid overdose, patients are most often treated by emergency medical services or bystanders with the opioid antagonist naloxone. Naloxone blocks the effects of opioids on the brain and may restore breathing within 2–8 min. While administration of naloxone can be lifesaving if administered early enough after an overdose, long-term treatment for OUD is needed as relapse rates and repeat overdose rates remain high [68_TD$IF][9]. Patients who are fortunate enough to survive an overdose are often in opioid withdrawal due to Acknowledgments the effects of naloxone and thus are often The authors thank the reviewers for constructive not amenable to referrals for substance comments. abuse treatment. Administration of buprenorphine offers an opportunity to Disclaimer Statement reduce symptoms of opioid withdrawal F.G.M. has grant support from Indivior in an emergency care setting that not only pharmaceuticals. should make patients feel better (less symptoms of withdrawal) but also should Resources offer patients some protection against an iwww.hhs.gov/opioids/about-the-epidemic/index. immediate repeat overdose if they were to html ii leave the ED and choose to use opioids www.cdc.gov/vitalsigns/opioid-overdoses/index. html again. iii www.nytimes.com/2018/08/18/health/
However, there are potential barriers to ED initiated buprenorphine after opioid overdose. First, most ED physicians do Traditionally, providers in the ED have not have the required Drug Enforcement treated the symptoms of the patient’s pre- Administration waiver to prescribe senting complaint but have not attempted buprenorphine. Furthermore, there are
opioid-addiction-treatment.html iv
www.deadiversion.usdoj.gov/pubs/docs/
dwp_buprenorphine.htm v
www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm619864.htm vi
www.fda.gov/newsevents/newsroom/
pressannouncements/ucm610807.htm
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12
999
vii
[ 6 9 _ T D $ D I F ] w ww.aha.org/system/files/content/17/
project-assert-case-study.pdf 1
Institute for Drug and Alcohol Studies, Virginia
Commonwealth University, Richmond, VA, USA *Correspondence: [email protected] (S.E. Johns). https://doi.org/10.1016/j.tips.2018.10.002 References 1. Substance Abuse and Mental Health Services Administration (SAMHSA) (2017) Key substance use and mental health indicators in the United States: results from the 2016 National Survey on Drug Use and Health. HHS Publication (SMA) 17-5044, Substance Abuse and Mental Health Services Administration 2. Morizio, K.M. et al. (2017) Characterization and management of patients with heroin versus nonheroin opioid overdoses: experience at an academic medical center. Pharmacotherapy 37, 781–790 3. D’Onofrio, G. et al. (2015) Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. JAMA 313, 1636–1644 4. Walsh, S. et al. (1995) Acute administration of buprenorphine in humans: partial agonist and blockade effects. J. Pharmacol. Exp. Ther. 274, 361–372 5. Bridge, P. et al. (2003) Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence. Drug Alcohol Depend. 70, S79–S85 6. Lowfall, M.R. and Walsh, S.L. (2014) A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J. Addict. Med. 8, 315–326 7. Soyka, M. (2015) Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update. Expert Opin. Drug Deliv. 12, 339–347 8. Duber, H.C. et al. (2018) Identification, management, and transition of care for patients with opioid use disorder in the emergency department. Ann. Emerg. Med. S0196–S0644, 30352–30354 9. Petry, N.M. and Bickel, W.K. (1999) Therapeutic alliance and psychiatric severity as predictors of completion of treatment for opioid dependence. Psychiatr. Serv. 50, 219–227
Series: Opioid Crisis
Science & Society
Development of New Analgesics: An Answer to Opioid Epidemic Tony L. Yaksh,1,* Matthew A. Hunt,1 and Gilson G. dos Santos1 Management of pain is a fundamental imperative in medicine. Current analgesics suffer from limitations related to efficacy and 1000
adverse events of which abuse potential has assumed an important role. Here we highlight the factors that drive the development of novel analgesics and the advances made in the field. Early Development of Analgesics Pain is ubiquitous, reflecting the Darwinian imperative that to survive, an organism avoids deleterious aspects of the environment. Management of the pain/aversive state has been an understandable preoccupation, ranging from laudanum and the purified product (morphine) and then recapitulated with molecular variants (heroin) and synthetic molecules (meperidine, methadone, and later fentanyl and carfentanil) [1]. In the 19th century, several nonopioid analgesics were created: aspirin, dipyrone, phenazone, and acetaminophen [2]. Despite the utility of these opiates/nonopiates in limiting pain, the limitations were appreciated early, including opiate dependence leading to the first opiate epidemic during the decade after the US Civil War. The nonopiates, while lacking abuse potential, were known for mechanism-limited efficacy and adverse events.
Factors Driving Development of New Analgesics
such as from a hot coffee cup; (ii) tissue injury/inflammation, where a pain state may covary with the onset and resolution of injury, and characterized by a complex behavioral phenotype of ongoing pain and an enhanced response to stimuli; and (iii) nerve injury that results in an ongoing pain state (dysesthesia) and an enhanced response to light touch or cold. These systems, reviewed extensively elsewhere, display considerable variation in their regulatory biology, such that drug targets effective in regulating one set of mechanisms may not regulate another [4]. Limited Efficacy for a Given Clinical Pain State Analgesics may fail in a clinical trial as a result of inadequate target engagement. Drug dosing necessary for target engagement may be inadequate because of adverse events precluding the use of higher doses or the trial may fail statistically because of a high placebo [5]. Further, clinical pain states, unlike the animal model, may simultaneously engage multiple mechanisms or involve mechanisms that change over time. For example, after tissue wounding has resolved, changes may occur in neural function, which leads to a neuropathic phenotype and pain states initiated by higher systems underlying learned associations (e.g., the memory) yielding an aversive internal experience [e.g., post-traumatic stress disorder (PTSD)] [6]. Accordingly, approaches to these pain states may require interventions that are directed at multiple targets. An example is pain associated with cancer, where well-managed patient care may include concurrent administration of multiple pain medications.
In the past 40 years, additional drug classes have been developed that manage tissue and nerve injury pain states with varying degrees of efficacy. Such nonopioid agents alter central nervous system (CNS) pain processing by interacting with specific receptors and channels that regulate the processing of pain information. Although of clear therapeutic utility, all are beset by limited activity and side effects [3]. Four factors drive the search for new Loss of Analgesic Activity Over Time analgesics. Analgesic drug tolerance is a well-recognized phenomenon and may arise Heterologous Mechanisms Underlying because of: (i) changes in the coupling Pain Phenotypes of drug action to signaling in nociceptive Pain may arise from three conditions: (i) (pain) pathways; and (ii) system changes acute, potentially tissue-damaging stimuli, in the face of chronic analgesic therapy
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12
Series: Opioid Crisis
Science & Society
Utilizing Buprenorphine in the Emergency Department after Overdose Sade E. Johns ,1,* Mary Bowman,1 and F. Gerard Moeller1 The United States is currently in the midst of an opioid epidemic. Barriers to treatment in the emergency department can lead to missed opportunities for helping prevent overdose and relapse in individuals with opioid use disorder. The administration of buprenorphine in the emergency department can potentially lead to better treatment outcomes for these individuals. The Opioid Epidemic The United States is in the midst of an opioid misuse epidemic. There has been a steady and dramatic increase in opioid-related overdose deaths in the United States over the past 10 years, with more than 42 000 overdose deaths in 2016i. A 2016 report estimated that 998
about 11.8 million people aged 12 years or older had misused opioids in the previous year [1]. Both prescription opioid use and heroin use have also increased in the United States. In 2016, an estimated 626 000 people had a heroin use disorder and an estimated 2.1 million people had a prescription drug use disorder [1]. This rise in prescription opioid misuse and heroin misuse has led to an increase in opioid-related deaths and overdose. This increase has also led to a strain in emergency departments (EDs). From July 2016 to September 2017, visits for opioid-related overdoses rose 30% in the United Statesii. Recent data show that many opioid overdose victims will have a repeat overdose event after ED admittance without outpatient treatment [2]. Current treatment referral procedures from the ED are insufficient, with only 37% of ED referrals leading to treatment engagement at 30 days post the initial encounter with a simple referral to outpatient treatment [3]. As recently reported in the New York Timesiii, there is a growing interest in the use of buprenorphine, a partial m-opioid agonist, in the ED setting for the treatment of opioid addiction. It is our opinion that the use of buprenorphine in the ED after opioid overdose may lead to better treatment retention and lower risk of repeat overdose.
Buprenorphine and Buprenorphine/Naloxone Buprenorphine is a partial m-opioid agonist that is approved by the FDA for the treatment of opioid use disorder (OUD). It has been shown to reduce withdrawal during opioid abstinence and reduce the risk of overdose [4]. As a partial agonist at the m-opioid receptor, buprenorphine has lower risk of overdose than other full agonists, such as methadone or oxycodone [4]. The approval of buprenorphine by the FDA for office-based
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12
treatment; the passage of the Drug Abuse Treatment Act of 2000 (DATA 2000) that allows qualified physicians to prescribe buprenorphineiv; and support from the National Institute on Drug Abuse allowed for buprenorphine to be used to treat OUDs in an office-based setting. By contrast, methadone can only be dispensed in a federally regulated methadone clinic. This, in turn, expanded the access to treatment for opioid dependence [5]. However, while buprenorphine has a lower abuse potential than other opioids, there are concerns about its misuse and diversion [6]. Because of these concerns, buprenorphine has now been made available in several formulations including the addition of a buprenorphine/naloxone combination. In 2003, a combination of buprenorphine with the opioid antagonist naloxone (Suboxone1) was marketed for the treatment of opioid dependence. This combination tablet was created to help reduce the misuse and abuse of buprenorphine through intravenous use and was to be administered sublingually (applied under the tongue). The addition of naloxone deters misuse because if taken in another route such as via injection, naloxone can precipitate withdrawal symptoms in opioid-dependent individuals. Furthermore, a film form of buprenorphine/naloxone was licensed in the United States in 2010. The film also deters misuse as its form makes it least likely to be taken in an unprescribed route such as intravenously or through snorting [7]. The FDA has recently approved the buprenorphine/naloxone combination film Cassipa1 for treatment of opioid dependencev. Both Cassipa and Suboxone have FDA approval for name brand as well as generic formsv,vi.
Treating Patients with OUD in the ED While EDs across the United States provide daily high-quality acute care to those
in need, they are increasingly becoming overcrowded from being frequently used as an entry point for people seeking care for non-urgent and/or chronic medical conditions. This is particularly true for vulnerable populations with limited resources, including many individuals with OUD. Situated on the front lines of the national opioid crisis, EDs treat opioid overdoses and the complications of OUD and addiction daily. These complications can include conditions such as skin infections from injection of opioids and withdrawal symptoms such as nausea, vomiting, and diarrhea. Despite being involved with opioid abuse patients frequently, there are many challenges in an emergency care setting that providers face to truly help those who struggle with addiction. Currently, the primary option available to the patients who present to the ED and request assistance with opioid abuse is a referral to outpatient addiction treatment services [3]. Given the rapid pace of a typical ED, providers may not have time to provide opioid counseling, assist in helping patients with engaging in care in an inpatient or outpatient treatment center, or be able to customize resources to the patient’s specific needs related to his or her current substance use disordervii[6_TD$IF]. The transition of care from the ED to a substance abuse treatment center is a high-risk time for patients, and coordinated care is essential to limit the potential for opioid withdrawal and relapse. While there is considerable attention focused on the opioid epidemic itself, there has been less emphasis on establishing best practices for treatment of OUD in an ED setting or for transitioning patients with OUD from the ED to appropriate substance abuse services such as inpatient rehabilitation centers or outpatient medicationassisted therapy centers [67_TD$IF][8].
to initiate long-term treatment for OUD. A 2015 study by D’Onofrio et al. [3] showed that when patients in the ED were given buprenorphine in conjunction with a brief intervention and an outpatient referral, the number of patients who continued to engage in substance abuse treatment was significantly higher than for those who were only given a referral or had a brief intervention and a referral. In our opinion, initiating substance abuse treatment with medications such as buprenorphine in the ED setting, a fairly new concept, can help prevent future relapse.
Use of Buprenorphine in ED to Prevent Opioid Relapse
concerns that using buprenorphine in the ED will dramatically increase ED visits due to the lack of outpatient buprenorphine providers. In addition, apart from opioid misuse, treatment of comorbidities such as chronic pain and psychiatric illness also need evaluation and post-ED treatment in such patients. A resolution of these issues will require a more direct connection between ED and outpatient treatment for opioid addiction. Moreover, before using buprenorphine in patients with OUD in the ED setting, pertinent questions will need to be addressed. These questions include: what percentage of patients who survive opioid overdose are willing to initiate buprenorphine in the ED; what doses and formulations achieve the best follow-up treatment engagement; and what is the timeline needed for outpatient follow-up visits post opioid overdose? However, despite these barriers and remaining questions, we believe that ED-initiated buprenorphine treatment post opioid overdose provides a potential novel method to potentially break the cycle of repeat opioid overdose and death.
Before arrival in the ED after an opioid overdose, patients are most often treated by emergency medical services or bystanders with the opioid antagonist naloxone. Naloxone blocks the effects of opioids on the brain and may restore breathing within 2–8 min. While administration of naloxone can be lifesaving if administered early enough after an overdose, long-term treatment for OUD is needed as relapse rates and repeat overdose rates remain high [68_TD$IF][9]. Patients who are fortunate enough to survive an overdose are often in opioid withdrawal due to Acknowledgments the effects of naloxone and thus are often The authors thank the reviewers for constructive not amenable to referrals for substance comments. abuse treatment. Administration of buprenorphine offers an opportunity to Disclaimer Statement reduce symptoms of opioid withdrawal F.G.M. has grant support from Indivior in an emergency care setting that not only pharmaceuticals. should make patients feel better (less symptoms of withdrawal) but also should Resources offer patients some protection against an iwww.hhs.gov/opioids/about-the-epidemic/index. immediate repeat overdose if they were to html ii leave the ED and choose to use opioids www.cdc.gov/vitalsigns/opioid-overdoses/index. html again. iii www.nytimes.com/2018/08/18/health/
However, there are potential barriers to ED initiated buprenorphine after opioid overdose. First, most ED physicians do Traditionally, providers in the ED have not have the required Drug Enforcement treated the symptoms of the patient’s pre- Administration waiver to prescribe senting complaint but have not attempted buprenorphine. Furthermore, there are
opioid-addiction-treatment.html iv
www.deadiversion.usdoj.gov/pubs/docs/
dwp_buprenorphine.htm v
www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm619864.htm vi
www.fda.gov/newsevents/newsroom/
pressannouncements/ucm610807.htm
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12
999
vii
[ 6 9 _ T D $ D I F ] w ww.aha.org/system/files/content/17/
project-assert-case-study.pdf 1
Institute for Drug and Alcohol Studies, Virginia
Commonwealth University, Richmond, VA, USA *Correspondence: [email protected] (S.E. Johns). https://doi.org/10.1016/j.tips.2018.10.002 References 1. Substance Abuse and Mental Health Services Administration (SAMHSA) (2017) Key substance use and mental health indicators in the United States: results from the 2016 National Survey on Drug Use and Health. HHS Publication (SMA) 17-5044, Substance Abuse and Mental Health Services Administration 2. Morizio, K.M. et al. (2017) Characterization and management of patients with heroin versus nonheroin opioid overdoses: experience at an academic medical center. Pharmacotherapy 37, 781–790 3. D’Onofrio, G. et al. (2015) Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. JAMA 313, 1636–1644 4. Walsh, S. et al. (1995) Acute administration of buprenorphine in humans: partial agonist and blockade effects. J. Pharmacol. Exp. Ther. 274, 361–372 5. Bridge, P. et al. (2003) Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence. Drug Alcohol Depend. 70, S79–S85 6. Lowfall, M.R. and Walsh, S.L. (2014) A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J. Addict. Med. 8, 315–326 7. Soyka, M. (2015) Buprenorphine-naloxone buccal soluble film for the treatment of opioid dependence: current update. Expert Opin. Drug Deliv. 12, 339–347 8. Duber, H.C. et al. (2018) Identification, management, and transition of care for patients with opioid use disorder in the emergency department. Ann. Emerg. Med. S0196–S0644, 30352–30354 9. Petry, N.M. and Bickel, W.K. (1999) Therapeutic alliance and psychiatric severity as predictors of completion of treatment for opioid dependence. Psychiatr. Serv. 50, 219–227
Series: Opioid Crisis
Science & Society
Development of New Analgesics: An Answer to Opioid Epidemic Tony L. Yaksh,1,* Matthew A. Hunt,1 and Gilson G. dos Santos1 Management of pain is a fundamental imperative in medicine. Current analgesics suffer from limitations related to efficacy and 1000
adverse events of which abuse potential has assumed an important role. Here we highlight the factors that drive the development of novel analgesics and the advances made in the field. Early Development of Analgesics Pain is ubiquitous, reflecting the Darwinian imperative that to survive, an organism avoids deleterious aspects of the environment. Management of the pain/aversive state has been an understandable preoccupation, ranging from laudanum and the purified product (morphine) and then recapitulated with molecular variants (heroin) and synthetic molecules (meperidine, methadone, and later fentanyl and carfentanil) [1]. In the 19th century, several nonopioid analgesics were created: aspirin, dipyrone, phenazone, and acetaminophen [2]. Despite the utility of these opiates/nonopiates in limiting pain, the limitations were appreciated early, including opiate dependence leading to the first opiate epidemic during the decade after the US Civil War. The nonopiates, while lacking abuse potential, were known for mechanism-limited efficacy and adverse events.
Factors Driving Development of New Analgesics
such as from a hot coffee cup; (ii) tissue injury/inflammation, where a pain state may covary with the onset and resolution of injury, and characterized by a complex behavioral phenotype of ongoing pain and an enhanced response to stimuli; and (iii) nerve injury that results in an ongoing pain state (dysesthesia) and an enhanced response to light touch or cold. These systems, reviewed extensively elsewhere, display considerable variation in their regulatory biology, such that drug targets effective in regulating one set of mechanisms may not regulate another [4]. Limited Efficacy for a Given Clinical Pain State Analgesics may fail in a clinical trial as a result of inadequate target engagement. Drug dosing necessary for target engagement may be inadequate because of adverse events precluding the use of higher doses or the trial may fail statistically because of a high placebo [5]. Further, clinical pain states, unlike the animal model, may simultaneously engage multiple mechanisms or involve mechanisms that change over time. For example, after tissue wounding has resolved, changes may occur in neural function, which leads to a neuropathic phenotype and pain states initiated by higher systems underlying learned associations (e.g., the memory) yielding an aversive internal experience [e.g., post-traumatic stress disorder (PTSD)] [6]. Accordingly, approaches to these pain states may require interventions that are directed at multiple targets. An example is pain associated with cancer, where well-managed patient care may include concurrent administration of multiple pain medications.
In the past 40 years, additional drug classes have been developed that manage tissue and nerve injury pain states with varying degrees of efficacy. Such nonopioid agents alter central nervous system (CNS) pain processing by interacting with specific receptors and channels that regulate the processing of pain information. Although of clear therapeutic utility, all are beset by limited activity and side effects [3]. Four factors drive the search for new Loss of Analgesic Activity Over Time analgesics. Analgesic drug tolerance is a well-recognized phenomenon and may arise Heterologous Mechanisms Underlying because of: (i) changes in the coupling Pain Phenotypes of drug action to signaling in nociceptive Pain may arise from three conditions: (i) (pain) pathways; and (ii) system changes acute, potentially tissue-damaging stimuli, in the face of chronic analgesic therapy
Trends in Pharmacological Sciences, December 2018, Vol. 39, No. 12