General Considerations

**3**

behaviors.

**Chapter 1**

and Risks

*Pilar Almela*

**1. Introduction**

hydrochloride.

syringe in the mid-nineteenth century.

in a less intense way [7].

be a minor medical problem.

Introductory Chapter: Opioid

Opiates have been used for various purposes throughout history [1, 2] (**Figure 1**). Interest in opium poppy plant (*Papaver somniferum*) arose more than 4500 years ago, due to the nutritional power of its seeds. Afterwards, around 1550 BC, opium was used in the Eastern Mediterranean and Egypt for religious and medicinal purposes. Greek medicine was the first to refer to opium as a narcotic, and it is at this time that a classification of the various preparations of this plant begins. In the seventeenth century, its use as a pain reliever in Sydenham's laudanum began to become general, until it was replaced by the currently used morphine

In 1803, the German pharmacist, Friedrich Wilhelm Adam Sertürner, identified and isolated the major psychoactive agent in opium, at approximately 4–21% and named it "morphium," alluding to the Greek god of dreams Morpheus [3]. Sertürner and three young assistant experimented the narcotic effects of morphine by taking the raw material. From this moment on, morphine began to be used for the same cases in which opium was used through different routes of administration (oral, rectal, or transdermal). Twenty years after Sertürner's discovery, in 1820, a pharmacist named Heinrich Emmanuel Merck began to commercialize morphine. The medical use of morphine was widespread after the discovery of the hypodermic

In 1973, three independent research groups headed by Solomon Snyder in Baltimore, Eric Simon in New York, and Lars Terenius in Sweden confirmed the existence of specific opioid receptors [4–6], and, 2 years later, Hughes discovered the presence of endogenous peptides able of activating the same receptors, although

The endogenous opioid system plays a main role in multiple physiological functions of the organism. When people carry out certain daily activities (eating, exercising, sexual behavior and others), endogenous opioids are released, inducing a brain reward effect that increases the likelihood that these behaviors tend to repeat. It is the so-called behavioral reinforcing effect, which can lead to addictive

Nowadays, morphine is widely used for chronic to severe pain relief in many conditions associated with heart attacks, serious injury, postoperative discomfort, and terminal illness such as cancer [8]. However, it is not possible to uncouple its beneficial analgesic effect from addiction, tolerance, and dependence. Being able to separate the potent analgesia from the addictive capacity would make pain relief to

Analgesics - History, Uses

### **Chapter 1**

## Introductory Chapter: Opioid Analgesics - History, Uses and Risks

*Pilar Almela*

### **1. Introduction**

Opiates have been used for various purposes throughout history [1, 2] (**Figure 1**). Interest in opium poppy plant (*Papaver somniferum*) arose more than 4500 years ago, due to the nutritional power of its seeds. Afterwards, around 1550 BC, opium was used in the Eastern Mediterranean and Egypt for religious and medicinal purposes. Greek medicine was the first to refer to opium as a narcotic, and it is at this time that a classification of the various preparations of this plant begins. In the seventeenth century, its use as a pain reliever in Sydenham's laudanum began to become general, until it was replaced by the currently used morphine hydrochloride.

In 1803, the German pharmacist, Friedrich Wilhelm Adam Sertürner, identified and isolated the major psychoactive agent in opium, at approximately 4–21% and named it "morphium," alluding to the Greek god of dreams Morpheus [3]. Sertürner and three young assistant experimented the narcotic effects of morphine by taking the raw material. From this moment on, morphine began to be used for the same cases in which opium was used through different routes of administration (oral, rectal, or transdermal). Twenty years after Sertürner's discovery, in 1820, a pharmacist named Heinrich Emmanuel Merck began to commercialize morphine. The medical use of morphine was widespread after the discovery of the hypodermic syringe in the mid-nineteenth century.

In 1973, three independent research groups headed by Solomon Snyder in Baltimore, Eric Simon in New York, and Lars Terenius in Sweden confirmed the existence of specific opioid receptors [4–6], and, 2 years later, Hughes discovered the presence of endogenous peptides able of activating the same receptors, although in a less intense way [7].

The endogenous opioid system plays a main role in multiple physiological functions of the organism. When people carry out certain daily activities (eating, exercising, sexual behavior and others), endogenous opioids are released, inducing a brain reward effect that increases the likelihood that these behaviors tend to repeat. It is the so-called behavioral reinforcing effect, which can lead to addictive behaviors.

Nowadays, morphine is widely used for chronic to severe pain relief in many conditions associated with heart attacks, serious injury, postoperative discomfort, and terminal illness such as cancer [8]. However, it is not possible to uncouple its beneficial analgesic effect from addiction, tolerance, and dependence. Being able to separate the potent analgesia from the addictive capacity would make pain relief to be a minor medical problem.

**Figure 1.** *Timeline of morphine history.*

### **2. Opioid receptors**

There are three main opioid receptor types that produce pharmacologic effects upon stimulation, mu (MOP), kappa (KOP), and delta (DOR), and morphine is a MOR-preferring agonist. The novel nociception/orphanin FQ receptor is considered to be a non-opioid branch of the opioid receptor family (**Figure 2**). However, substantial pharmacological evidence for additional opioid receptor phenotypes exists [9].

Opioid receptors are a group of Gi/Go protein-coupled receptors, which consist of seven transmembrane domains, three extracellular, and three intracellular loops, extracellular amino acid N-terminus, and intracellular carboxyl C-terminus. They are activated both by endogenously opioid peptides and by exogenously administered natural, synthetic, or semisynthetic opiate compounds such as morphine and heroin.

Opioid receptors are located in both the central and peripheral nervous system. Morphine analgesia is mainly due to its action on MOP receptors, although the activation of KOP and DOP receptors also participates in the analgesic effects of this drug. These receptors act synergistically in different places at CNS level, from the spinal cord to the cerebral cortex, inhibiting the nociceptive sensation whatever its location or intensity. Specifically, they act on the afferent system at the spinal level, where the activation of MOP receptors results in the inhibition of primary sensory fibers. Morphine also acts by regulating the transmission of the efferent system, inhibiting the nociceptive transmission sent from mesencephalic areas and the brainstem. Nevertheless, opiates not only diminish the painful sensation but also

**5**

euphoria prevails.

known as addiction.

ing drugs.

*Introductory Chapter: Opioid Analgesics - History, Uses and Risks*

and where a large number of opioid receptors are expressed.

**3. Genetic polymorphisms modulating the pain response**

and the changes described in the OPRM1 gene [12].

reduce the incidence of drug dependence and addiction.

**4. Opioid addiction: a severe substance use disorder**

responsible for the tremendous addictive capacity of this molecule.

block the unpleasant or distressing feelings that accompany pain through its action at the limbic and cortical level, areas involved in emotional physiological responses

Some pharmacological properties of opioid agonists are routinely used in clinic practice. In addition to the aforementioned opioid analgesic power, these drugs have utility in other conditions as cough suppressant, antidiarrheal, emetic, and anesthetics, being also used in special situations as in the acute pulmonary edema or in respiratory rhythm regulation in patients undergoing artificial respiration.

Recent research in the field of pharmacogenomics has discovered important single-nucleotide polymorphisms that are thought to be linked to opioid dose variability. This could explain the genetic changes in the analgesic opioid dose. These polymorphisms appear in several areas involved in pain pathways, drug receptors, drug-metabolizing enzymes, and drug efflux molecules [11]. Among the genetic polymorphisms identified as possible modulators of the pain response, we can mention genes that code for voltage-gated sodium channels, the metabolic enzyme catechol-O-methyltransferase (COMT), the synthetic enzyme CTP cyclohydrolase,

A better knowledge of these polymorphisms can help clinicians to manage interindividual variability in opioid demands. These genetic markers could also help to design tools to precisely predict the analgesic opioid dose, increase efficacy, and

Today, morphine is a Schedule II narcotic, along with other drugs like fentanyl, hydromorphone, meperidine, methadone, or oxycodone, under the Controlled Substances Act (US Drug Enforcement Administration) [13], and is available only by a prescription due to its high potential for abuse. Morphine is also regulated because it is the precursor to heroin, a synthetic alkaloid that presents a different pharmacokinetics than morphine, resulting in more acute CNS effects, partly

The first experiences with opioids are usually unpleasant, since the effects on the gastrointestinal tract (nausea and vomiting) predominate. However, when repeating the behavior, tolerance to the emetic action develops, then the feeling of

The addictive state is characterized by the compulsive consumption of the drug despite the serious negative consequences that it entails, such as diseases, neglecting social and family obligations, and the need to commit criminal acts to obtain the substance. For drug addicts, drugs become the main incentive within their scale of values, and, as a result, their lives are reduced to obtaining and consum-

In addition, drug addiction involves loss of control in limiting intake and emerging of a negative emotional state (e.g., dysphoria, anxiety and irritability), reflecting a motivational withdrawal syndrome when access to the drug is prevented [14]. The addictive process consists of three stages (**Figure 3**): binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving). These stages interact with each other, becoming more intense and ultimately leading to the state

*DOI: http://dx.doi.org/10.5772/intechopen.92401*

**Figure 2.** *Opioid receptor structures. Modified from [10].*

### *Introductory Chapter: Opioid Analgesics - History, Uses and Risks DOI: http://dx.doi.org/10.5772/intechopen.92401*

*Opioids - From Analgesic Use to Addiction*

**2. Opioid receptors**

*Timeline of morphine history.*

exists [9].

**Figure 1.**

and heroin.

There are three main opioid receptor types that produce pharmacologic effects upon stimulation, mu (MOP), kappa (KOP), and delta (DOR), and morphine is a MOR-preferring agonist. The novel nociception/orphanin FQ receptor is considered to be a non-opioid branch of the opioid receptor family (**Figure 2**). However, substantial pharmacological evidence for additional opioid receptor phenotypes

Opioid receptors are a group of Gi/Go protein-coupled receptors, which consist of seven transmembrane domains, three extracellular, and three intracellular loops, extracellular amino acid N-terminus, and intracellular carboxyl C-terminus. They are activated both by endogenously opioid peptides and by exogenously administered natural, synthetic, or semisynthetic opiate compounds such as morphine

Opioid receptors are located in both the central and peripheral nervous system.

Morphine analgesia is mainly due to its action on MOP receptors, although the activation of KOP and DOP receptors also participates in the analgesic effects of this drug. These receptors act synergistically in different places at CNS level, from the spinal cord to the cerebral cortex, inhibiting the nociceptive sensation whatever its location or intensity. Specifically, they act on the afferent system at the spinal level, where the activation of MOP receptors results in the inhibition of primary sensory fibers. Morphine also acts by regulating the transmission of the efferent system, inhibiting the nociceptive transmission sent from mesencephalic areas and the brainstem. Nevertheless, opiates not only diminish the painful sensation but also

**4**

**Figure 2.**

*Opioid receptor structures. Modified from [10].*

block the unpleasant or distressing feelings that accompany pain through its action at the limbic and cortical level, areas involved in emotional physiological responses and where a large number of opioid receptors are expressed.

Some pharmacological properties of opioid agonists are routinely used in clinic practice. In addition to the aforementioned opioid analgesic power, these drugs have utility in other conditions as cough suppressant, antidiarrheal, emetic, and anesthetics, being also used in special situations as in the acute pulmonary edema or in respiratory rhythm regulation in patients undergoing artificial respiration.

### **3. Genetic polymorphisms modulating the pain response**

Recent research in the field of pharmacogenomics has discovered important single-nucleotide polymorphisms that are thought to be linked to opioid dose variability. This could explain the genetic changes in the analgesic opioid dose. These polymorphisms appear in several areas involved in pain pathways, drug receptors, drug-metabolizing enzymes, and drug efflux molecules [11]. Among the genetic polymorphisms identified as possible modulators of the pain response, we can mention genes that code for voltage-gated sodium channels, the metabolic enzyme catechol-O-methyltransferase (COMT), the synthetic enzyme CTP cyclohydrolase, and the changes described in the OPRM1 gene [12].

A better knowledge of these polymorphisms can help clinicians to manage interindividual variability in opioid demands. These genetic markers could also help to design tools to precisely predict the analgesic opioid dose, increase efficacy, and reduce the incidence of drug dependence and addiction.

### **4. Opioid addiction: a severe substance use disorder**

Today, morphine is a Schedule II narcotic, along with other drugs like fentanyl, hydromorphone, meperidine, methadone, or oxycodone, under the Controlled Substances Act (US Drug Enforcement Administration) [13], and is available only by a prescription due to its high potential for abuse. Morphine is also regulated because it is the precursor to heroin, a synthetic alkaloid that presents a different pharmacokinetics than morphine, resulting in more acute CNS effects, partly responsible for the tremendous addictive capacity of this molecule.

The first experiences with opioids are usually unpleasant, since the effects on the gastrointestinal tract (nausea and vomiting) predominate. However, when repeating the behavior, tolerance to the emetic action develops, then the feeling of euphoria prevails.

The addictive state is characterized by the compulsive consumption of the drug despite the serious negative consequences that it entails, such as diseases, neglecting social and family obligations, and the need to commit criminal acts to obtain the substance. For drug addicts, drugs become the main incentive within their scale of values, and, as a result, their lives are reduced to obtaining and consuming drugs.

In addition, drug addiction involves loss of control in limiting intake and emerging of a negative emotional state (e.g., dysphoria, anxiety and irritability), reflecting a motivational withdrawal syndrome when access to the drug is prevented [14].

The addictive process consists of three stages (**Figure 3**): binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving). These stages interact with each other, becoming more intense and ultimately leading to the state known as addiction.

**Figure 3.** *Neurobiological bases of substance use disorders [14].*

In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), addiction is synonymous with a severe substance use disorder, and opioid use disorder is included here [15]. Just like it happens with other substance use disorders, individuals can begin opioid misuse with recreational use of the drug and evolve to the withdrawal/negative affect stage as negative reinforcement appear.

Despite numerous treatment attempts and the serious risk to their lives, relapses to drug-seeking and drug-taking behaviors following months or years of abstinence are frequent when addicts find stimuli associated with the first contact with the drug [16]. This fact shows that we need more effective long-term treatments for drug dependence and emphasizes, on the other hand, the importance of better understanding the neurobiological mechanisms that underlie drug addiction and their persistence.

### **5. The opioid epidemic: challenges and opportunities**

Over the past 20 years, there has been a significant increase in opioid prescription worldwide, but especially in the United States. This substantial increase in opioid prescribing patterns has been due, in part, to the influence of certain currents of opinion, which trivialized the potential drawbacks of opioid painkillers, along with the widely spread belief that any kind of pain could and should be treated with opioids. On the other hand, consuming higher doses than prescribed or by people who had not been prescribed, or switching to a more direct route of administration than the oral route, has contributed to the expansion of the abuse of these drugs among the population [17].

An opioid epidemic has been declared in 2017 in the United States [1, 18]. Europe and, particularly, low- and middle-income countries, appear to be less influenced by this problem. An estimated 10.3 million Americans aged 12 and older misused opioids in 2018, including 9.9 million prescription pain reliever (morphine, oxycodone, and hydrocodone) abusers and 808,000 heroin users. A report from the Centers for Disease Control and Prevention (CDC) indicated that opioid

**7**

**Author details**

\*Address all correspondence to: palmela@um.es

provided the original work is properly cited.

Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Pilar Almela

Spain

*Introductory Chapter: Opioid Analgesics - History, Uses and Risks*

sales multiplied by 14 from 1999 to 2010. Moreover, this center reported that, in 2017, the number of overdose deaths involving opioids (including prescription and illegal opioids) was six times higher than in 1999. Prescription opioid overdose, abuse, and dependence involve high economic costs for American society from

Avoiding prescription of opioid pain relievers when its therapeutic indication is doubtful or unnecessary is always easier than proceeding later upon treatments for abuse, which will be even more difficult if the patient is not involved. Only in certain situations, opioid administration for pain relieve is essential; for all the others, a great diversity of interventions that can be as effective or more than the prescription of opioids are available, avoiding thus the potential risks of addiction

Different states have begun implementing prescription drug monitoring programs to control irregular prescribing practices by clinicians and the recreational use of opioids. In addition, current strategies include a greater involvement of healthcare professionals (such as psychiatrists) and approaches to address comorbidities [19]. These measures could be resulting in a decrease in opioid prescription, as shown in last reports from CDC, which indicate a reduction in these prescrip-

and overdose that are associated with the consumption of opiates.

*DOI: http://dx.doi.org/10.5772/intechopen.92401*

around \$78.5 billion.

tions from 2016 [20].

### *Introductory Chapter: Opioid Analgesics - History, Uses and Risks DOI: http://dx.doi.org/10.5772/intechopen.92401*

*Opioids - From Analgesic Use to Addiction*

*Neurobiological bases of substance use disorders [14].*

In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), addiction is synonymous with a severe substance use disorder, and opioid use disorder is included here [15]. Just like it happens with other substance use disorders, individuals can begin opioid misuse with recreational use of the drug and evolve to the

Despite numerous treatment attempts and the serious risk to their lives, relapses to drug-seeking and drug-taking behaviors following months or years of abstinence are frequent when addicts find stimuli associated with the first contact with the drug [16]. This fact shows that we need more effective long-term treatments for drug dependence and emphasizes, on the other hand, the importance of better understanding the neurobiological mechanisms that underlie drug addiction and

Over the past 20 years, there has been a significant increase in opioid prescription worldwide, but especially in the United States. This substantial increase in opioid prescribing patterns has been due, in part, to the influence of certain currents of opinion, which trivialized the potential drawbacks of opioid painkillers, along with the widely spread belief that any kind of pain could and should be treated with opioids. On the other hand, consuming higher doses than prescribed or by people who had not been prescribed, or switching to a more direct route of administration than the oral route, has contributed to the expansion of the abuse of these drugs

An opioid epidemic has been declared in 2017 in the United States [1, 18]. Europe and, particularly, low- and middle-income countries, appear to be less influenced by this problem. An estimated 10.3 million Americans aged 12 and older misused opioids in 2018, including 9.9 million prescription pain reliever (morphine, oxycodone, and hydrocodone) abusers and 808,000 heroin users. A report from the Centers for Disease Control and Prevention (CDC) indicated that opioid

withdrawal/negative affect stage as negative reinforcement appear.

**5. The opioid epidemic: challenges and opportunities**

**6**

their persistence.

**Figure 3.**

among the population [17].

sales multiplied by 14 from 1999 to 2010. Moreover, this center reported that, in 2017, the number of overdose deaths involving opioids (including prescription and illegal opioids) was six times higher than in 1999. Prescription opioid overdose, abuse, and dependence involve high economic costs for American society from around \$78.5 billion.

Avoiding prescription of opioid pain relievers when its therapeutic indication is doubtful or unnecessary is always easier than proceeding later upon treatments for abuse, which will be even more difficult if the patient is not involved. Only in certain situations, opioid administration for pain relieve is essential; for all the others, a great diversity of interventions that can be as effective or more than the prescription of opioids are available, avoiding thus the potential risks of addiction and overdose that are associated with the consumption of opiates.

Different states have begun implementing prescription drug monitoring programs to control irregular prescribing practices by clinicians and the recreational use of opioids. In addition, current strategies include a greater involvement of healthcare professionals (such as psychiatrists) and approaches to address comorbidities [19]. These measures could be resulting in a decrease in opioid prescription, as shown in last reports from CDC, which indicate a reduction in these prescriptions from 2016 [20].

### **Author details**

Pilar Almela Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain

\*Address all correspondence to: palmela@um.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Devereaux AL, Mercer SL, Cunningham CW. DARK classics in chemical neuroscience: Morphine. ACS Chemical Neuroscience. 2018;**9**:2395-2407. DOI: 10.1021/ acschemneuro.8b00150

[2] Presley CC, Lindsley CW. DARK Classics in chemical neuroscience: Opium, a historical perspective. ACS Chemical Neuroscience. 2018;**9**:2503-2518. DOI: 10.1021/ acschemneuro.8b00459

[3] Sertürner F. Säure im Opium. Journal Der Pharmacie. 1805;**13**:229-243

[4] Pert CB, Snyder SH. Opiate receptor: Demonstration in nervous tissue. Science. 1973;**179**:1011-1074. DOI: 10.1126/science.179.4077.1011

[5] Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H]etorphine to rat brain homogenate. Proceedings of the National Academy of Sciences of the United States of America. 1973;**70**: 1947-1949. DOI: 10.1073/pnas.70.7.1947

[6] Terenius L. Stereospecific interaction between narcotic analgesics and synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacologica et Toxicologica. 1973;**32**:317-320. DOI: 10.1111/j.1600-0773.1973.tb01477.x

[7] Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morrisa HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975;**258**:577-579. DOI: 10.1038/258577a0

[8] Sverrisdottir E, Lund TM, Olesen AE, Drewes AM, Christrup LL, Kreilgaard M. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and

clinical pain. European Journal of Pharmaceutical Sciences. 2015;**74**:45-62. DOI: 10.1016/j.ejps. 2015.03.020

[9] Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annual Review of Biochemistry. 2004;**73**: 953-990. DOI: 10.1146/annurev. biochem.73.011303.073940

[10] Manglik A. Molecular basis of opioid action: From structures to new leads. Biological Psychiatry. 2020;**87**:6-14. DOI: 10.1016/j.biopsych.2019.08.028

[11] Kumar S, Kundra P, Ramsamy K, Surendiran A. Pharmacogenetics of opioids: A narrative review. Anaesthesia. 2019;**74**:1456-1470. DOI: 10.1111/anae.14813

[12] Cornett EM, MAC T, Pinner A, Thakur P, TSG S, Siddaiah H, et al. Pharmacogenomics of pain management: The impact of specific biological polymorphisms on drugs and metabolism. Current Oncology Reports. 2020;**22**:18. DOI: 10.1007/ s11912-020-0865-4

[13] U.S. Department of Justice. Drug Enforcement Administration. A DEA Resource Guide. 2017 ed. 2017. Available from: https://www.dea.gov/sites/ default/files/sites/getsmartaboutdrugs. com/files/publications/DoA\_2017Ed\_ Updated\_6.16.17.pdf#page=45

[14] Koob GF. Neurobiology of opioid addiction: Opponent process, hyperkatifeia, and negative reinforcement. Biological Psychiatry. 2020;**87**:44-53. DOI: 10.1016/j. biopsych.2019.05.023

[15] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013

**9**

*Introductory Chapter: Opioid Analgesics - History, Uses and Risks*

*DOI: http://dx.doi.org/10.5772/intechopen.92401*

[17] Kaye AD, Jones MR, Kaye AM, Ripoll JG, Galan V, Beakley BD, et al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician.

[18] Morrow JB, Ropero-Miller JD, Catlin ML, Winokur AD, Cadwallader AB,

epidemic: Moving toward an integrated, holistic analytical response. Journal of Analytical Toxicology. 2019;**43**:1-9. DOI:

Staymates JL, et al. The opioid

[19] Volkow ND, Blanco C. The changing opioid crisis: Development, challenges and opportunities. Molecular

Psychiatry. 2020. DOI: 10.1038/

[20] Annual Surveillance Report of Drug-Related Risks and Outcomes. United States: CDC National Center for Injury Prevention and Control. 2019. Available from: https://www.cdc.gov/ drugoverdose/pdf/pubs/2019-cdc-drug-

[16] Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;**35**:217-238. DOI: 10.1038/

npp.2009.110

2017;**20**:S93-S109

10.1093/jat/bky049

s41380-020-0661-4

surveillance-report.pdf

*Introductory Chapter: Opioid Analgesics - History, Uses and Risks DOI: http://dx.doi.org/10.5772/intechopen.92401*

[16] Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;**35**:217-238. DOI: 10.1038/ npp.2009.110

[17] Kaye AD, Jones MR, Kaye AM, Ripoll JG, Galan V, Beakley BD, et al. Prescription opioid abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse: Part 1. Pain Physician. 2017;**20**:S93-S109

[18] Morrow JB, Ropero-Miller JD, Catlin ML, Winokur AD, Cadwallader AB, Staymates JL, et al. The opioid epidemic: Moving toward an integrated, holistic analytical response. Journal of Analytical Toxicology. 2019;**43**:1-9. DOI: 10.1093/jat/bky049

[19] Volkow ND, Blanco C. The changing opioid crisis: Development, challenges and opportunities. Molecular Psychiatry. 2020. DOI: 10.1038/ s41380-020-0661-4

[20] Annual Surveillance Report of Drug-Related Risks and Outcomes. United States: CDC National Center for Injury Prevention and Control. 2019. Available from: https://www.cdc.gov/ drugoverdose/pdf/pubs/2019-cdc-drugsurveillance-report.pdf

**8**

*Opioids - From Analgesic Use to Addiction*

[1] Devereaux AL, Mercer SL, Cunningham CW. DARK classics in chemical neuroscience: Morphine. ACS Chemical Neuroscience. 2018;**9**:2395-2407. DOI: 10.1021/

clinical pain. European Journal of Pharmaceutical Sciences. 2015;**74**:45-62.

DOI: 10.1016/j.ejps. 2015.03.020

Whistler JL. Opioid receptors. Annual Review of Biochemistry. 2004;**73**: 953-990. DOI: 10.1146/annurev. biochem.73.011303.073940

[10] Manglik A. Molecular basis of opioid action: From structures to new leads. Biological Psychiatry. 2020;**87**:6-14. DOI:

[9] Waldhoer M, Bartlett SE,

10.1016/j.biopsych.2019.08.028

opioids: A narrative review.

10.1111/anae.14813

s11912-020-0865-4

[11] Kumar S, Kundra P, Ramsamy K, Surendiran A. Pharmacogenetics of

Anaesthesia. 2019;**74**:1456-1470. DOI:

[12] Cornett EM, MAC T, Pinner A, Thakur P, TSG S, Siddaiah H, et al. Pharmacogenomics of pain management: The impact of specific biological polymorphisms on drugs and metabolism. Current Oncology Reports. 2020;**22**:18. DOI: 10.1007/

[13] U.S. Department of Justice. Drug Enforcement Administration. A DEA Resource Guide. 2017 ed. 2017. Available from: https://www.dea.gov/sites/ default/files/sites/getsmartaboutdrugs. com/files/publications/DoA\_2017Ed\_

Updated\_6.16.17.pdf#page=45

[14] Koob GF. Neurobiology of opioid addiction: Opponent

biopsych.2019.05.023

2013

process, hyperkatifeia, and negative reinforcement. Biological Psychiatry. 2020;**87**:44-53. DOI: 10.1016/j.

[15] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing;

[2] Presley CC, Lindsley CW. DARK Classics in chemical neuroscience: Opium, a historical perspective. ACS Chemical Neuroscience. 2018;**9**:2503-2518. DOI: 10.1021/

[3] Sertürner F. Säure im Opium. Journal

[4] Pert CB, Snyder SH. Opiate receptor: Demonstration in nervous tissue. Science. 1973;**179**:1011-1074. DOI: 10.1126/science.179.4077.1011

Der Pharmacie. 1805;**13**:229-243

[5] Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic [3H]etorphine to rat brain homogenate. Proceedings of the National Academy of Sciences of the United States of America. 1973;**70**: 1947-1949. DOI: 10.1073/pnas.70.7.1947

[6] Terenius L. Stereospecific interaction

Morgan BA, Morrisa HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975;**258**:577-579. DOI:

Olesen AE, Drewes AM, Christrup LL, Kreilgaard M. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and

between narcotic analgesics and synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacologica et Toxicologica. 1973;**32**:317-320. DOI: 10.1111/j.1600-0773.1973.tb01477.x

[7] Hughes J, Smith TW, Kosterlitz HW, Fothergill LA,

[8] Sverrisdottir E, Lund TM,

10.1038/258577a0

acschemneuro.8b00150

**References**

acschemneuro.8b00459

Section 2

Opioid Uses

Section 2 Opioid Uses

**Chapter 2**

A New Paradigm: Prevention of

Management through Minimizing

Current exacerbations of chronic pain cannot be understood in isolation from how past incidents impact pain and its experience. Patients who frequent the Emergency Room or hospital for a pain crisis or intensification of their pain without new findings on X-rays or scans are often seen as 'drug seekers.' Yet, to the patient the pain is agonizing, and the suffering real. It is this type of patient that prompted an ongoing improvement project in our local hospital, our Multiple Visit Patient Complex Care Program. The goal was to determine the similarities between this type of 'complex' patient—who frequents the hospital despite no new radiographic change—and other patients. Understanding this 'complex' pattern in terms of central intractable pain can change the trajectory of treatment. Results of our program described here reveal that a better understanding of central pain and central sensi-

**Keywords:** opioids, central sensitization, central intractable pain, trauma,

Patient complaints of pain can befuddle even the most experienced healthcare provider. The seeming lack of an organic origin, along with multiple exacerbating affective and cognitive variables can result in stopgap measures and incomplete or inaccurate diagnoses. The costs of this approach to treatment can be significant. Broadly speaking, misdiagnoses or inadequate contribute to overall runaway healthcare costs. The cost of pain care is exorbitant already; inaccurate diagnoses can result in money spent for the wrong treatment: 'The annual cost of pain was greater than the annual costs in 2010 dollars of heart disease (\$309 billion), cancer (\$243 billion), and diabetes (\$188 billion) and nearly 30% higher than the combined

For individual patients who do not receive an accurate diagnosis of their pain, there is a risk of a redundancy of testing that can result in increased exposure to radiation, risk of further misdiagnosis, and mistreatment. The primary risk to the patient, however, is the development of debility, immobility, and isolation. The reasons for inadequate pain diagnoses are sometimes attributed to the patients themselves. Many times, patients are labeled as 'drug seekers' when they

Central Sensitization in Pain

Opioid Exposure

tization can result in better patient care.

**1. Introduction: the costs of misdiagnosing pain**

multi-modal pain management

cost of cancer and diabetes' [1].

**13**

*Pamela Bolyanatz*

**Abstract**

### **Chapter 2**

## A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing Opioid Exposure

*Pamela Bolyanatz*

### **Abstract**

Current exacerbations of chronic pain cannot be understood in isolation from how past incidents impact pain and its experience. Patients who frequent the Emergency Room or hospital for a pain crisis or intensification of their pain without new findings on X-rays or scans are often seen as 'drug seekers.' Yet, to the patient the pain is agonizing, and the suffering real. It is this type of patient that prompted an ongoing improvement project in our local hospital, our Multiple Visit Patient Complex Care Program. The goal was to determine the similarities between this type of 'complex' patient—who frequents the hospital despite no new radiographic change—and other patients. Understanding this 'complex' pattern in terms of central intractable pain can change the trajectory of treatment. Results of our program described here reveal that a better understanding of central pain and central sensitization can result in better patient care.

**Keywords:** opioids, central sensitization, central intractable pain, trauma, multi-modal pain management

### **1. Introduction: the costs of misdiagnosing pain**

Patient complaints of pain can befuddle even the most experienced healthcare provider. The seeming lack of an organic origin, along with multiple exacerbating affective and cognitive variables can result in stopgap measures and incomplete or inaccurate diagnoses. The costs of this approach to treatment can be significant.

Broadly speaking, misdiagnoses or inadequate contribute to overall runaway healthcare costs. The cost of pain care is exorbitant already; inaccurate diagnoses can result in money spent for the wrong treatment: 'The annual cost of pain was greater than the annual costs in 2010 dollars of heart disease (\$309 billion), cancer (\$243 billion), and diabetes (\$188 billion) and nearly 30% higher than the combined cost of cancer and diabetes' [1].

For individual patients who do not receive an accurate diagnosis of their pain, there is a risk of a redundancy of testing that can result in increased exposure to radiation, risk of further misdiagnosis, and mistreatment. The primary risk to the patient, however, is the development of debility, immobility, and isolation.

The reasons for inadequate pain diagnoses are sometimes attributed to the patients themselves. Many times, patients are labeled as 'drug seekers' when they come to the Emergency Department complaining of pain. If patients are presumed to be drug seekers, and if opiates are the easy default treatment for pain, this combination can easily lead to a resistance, even if not entirely conscious—on the part of healthcare staff to assume that the pain is overstated, or perhaps even utterly absent. The ready use of opiates, then, does have to be seen as a contributing problem to pain misdiagnoses. This predisposition has its own set of costs.

But medical providers are not the only piece of the puzzle. National pharmacy

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing…*

A postoperative patient changed pharmacies shortly after surgery. He was able to receive the first 7 days of medication, but while the pharmacy was waiting for a phone call to complete his authorization, he did not have access to his regularly prescribed medication. This contributed to a pain crisis and he was hospitalized for 3 days. With his regular opioid medication dosage, the admission could have been prevented. The patient was not misusing his medication; he was affected by a ruling that was put in place to safeguard opioid medication from getting in to the hands of those who do not need a large quantity of

Many state surgical organizations are taking notice of the overprescribing on the part of their members in the past. A not uncommon unintended consequence of this practice has been for post-operative patients, historically, to take a few oral pain relievers, and then the rest of the bottle of hydrocodone (Norco™, Vicodin) or oxycodone (Percocet™) sits in the medicine cupboard for many years. The result is that many household opioid supplies allow patients to self- and over-medicate in ways that "fly under the radar" of healthcare personnel. Case Study 3 is one such instance:

A patient arrived at the Emergency Room in clear distress from her new onset pneumonia. She was experiencing significant chest discomfort, and asked for pain medications since her hydrocodone with acetaminophen 7.5/325 mg was not working; the patient felt that something stronger was needed, and so insisted on a stronger dose. Emergency Room providers do not routinely administer opioids for pneumonia, so she left the hospital against medical advice, frustrated that her pain was not controlled. She eventually

Ossipov et al. [4] found the experience of pain to be influenced by emotions and experiences. Painful experiences accompanied by intense emotions, such as wartime injuries, or co-occurring mental health disorders play a role in the body's

Pain perception and modulation are important concepts to understand within

The following is not an exhaustive list of some of the complexities of the experience of pain; they are offered to show that today's pain management provider must be something of a jack-of-all-trades in order to understand the nature and

• *Multiple medications are often utilized in the management of pain*. Antidepressants, anti-inflammatories, and bowel medications are all important parts of the picture. Some are finding that topical treatments can be effective in the treatment of pain. It can be a burden to maintain a working knowledge of the plethora of available options, in order to be able to utilize the most effective pain

• *There are not enough pain specialists*. There is a disparity between the number of pain specialists and the number of patients in pain. Pain patients sense, not

returned due to her worsening pneumonia symptoms, which resulted in hospitalization.

own endogenous inhibitory system in heightening the pain perception.

**3. Factors that affect the experience of pain**

pain management and its treatment, as in **Figure 1**.

medications, especially if one is not a pain specialist.

chains have placed restrictions of 7 days for the first prescription of opioids, regardless of whether the patient is opioid naïve or opioid tolerant. This can have

unintended outcomes, exemplified by Case Study 2:

*DOI: http://dx.doi.org/10.5772/intechopen.85192*

**Case Study 2**

**Case Study 3**

treatment of pain.

**15**

opioid medication (from Ref. [3]).

For example, patients may have neurobiological anomalies, in which there is an anxiety, fear, and pain matrix in the prefrontal cortex and amygdala. This is influenced by neurotransmitters and glial cell activation, which can lead to pervasive inflammation and central sensitivity. It is paramount that hospitals utilize nonopioid and multi-modal treatments after surgeries to reduce opioid exposure of the brain. The exposure of the insula and the limbic area of the brain to morphine or hydromorphone begins the cascade of blocking endogenous opioid production.

In fact, 20% of patients complaining of pain have likely used illicit substances, and may be found to have psychiatric or opioid use disorders that are not accurately diagnosed and miss proper treatment with medical-assisted drug therapy. Sporadic follow-up, and missed opportunities to begin treatment due to the health care providers judgment and stigma, can lead to becoming stuck in the same cycle [2].

Ultimately, it is vital to determine a patient's full history. Displays of judgment that evoke a patient's sense of being stigmatized will more likely lead to an improper diagnosis and treatment by the healthcare team. If a treatment is not effective, then understanding the options to reassess and change the course of treatment become necessary. Opioid administration guidelines have been slowly changing since 2005 with the concept of 'not every increase in pain should be met with a higher dose of narcotics (opioids)' [3]. Further research into hormonal, dietary, and other natural or integrative methods of the treatment of pain is increasingly necessary, especially as the costs of opioid use for misdiagnosed pain become more widely known.

### **2. Current practices in pain treatment**

Today healthcare providers are working to lower opioid use in their own way, some in systemized fashion, while other just draw a line in their practice and hope that patients' pain improves, and/or that the patients get tired of asking for medication. But the use of opioids, especially, in pain management today is a complex landscape.

Pain and the treatment or management of pain is a widely debated subject. It is typically not a favorite topic of most providers; many feel they were not trained to care for the wide variety of pain complaints and some throw their hands up in frustration at the myriad of complaints they hear. Some providers have changed their office policy to include a blanket statement, "I do not prescribe narcotics." The reason for this policy, gleaned through many conversations with providers, is that they prefer to avoid the many 'headaches' from the 'drug seekers.' Case Study 1 illustrates this problem.

### **Case Study 1**

A patient arrives at the Emergency Department with no external presenting problems, but she describes her internal pain as, 'I feel like I am going to break apart.' She had undergone surgery 1 week prior, a straightforward laparoscopic cholecystectomy, but she is sure there is an infection or something worse inside. The staff in the Emergency Room see her often for her anxiety; they have other patients with 'true' emergencies in the rooms next door. Should she receive opioids for her pain? She and others like her struggle with feelings of anxiety, fear, pain and often come to the Emergency Department for relief. On a daily basis, patients with chronic pain feel their pain in a way that is difficult to express to others. Their previous experiences of anxiety, trauma, chronic disease, and previous treatment with opioids influence their current situation.

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing… DOI: http://dx.doi.org/10.5772/intechopen.85192*

But medical providers are not the only piece of the puzzle. National pharmacy chains have placed restrictions of 7 days for the first prescription of opioids, regardless of whether the patient is opioid naïve or opioid tolerant. This can have unintended outcomes, exemplified by Case Study 2:

### **Case Study 2**

come to the Emergency Department complaining of pain. If patients are presumed to be drug seekers, and if opiates are the easy default treatment for pain, this combination can easily lead to a resistance, even if not entirely conscious—on the part of healthcare staff to assume that the pain is overstated, or perhaps even utterly absent. The ready use of opiates, then, does have to be seen as a contributing problem to pain misdiagnoses. This predisposition has its own set of costs.

For example, patients may have neurobiological anomalies, in which there is an

In fact, 20% of patients complaining of pain have likely used illicit substances, and may be found to have psychiatric or opioid use disorders that are not accurately diagnosed and miss proper treatment with medical-assisted drug therapy. Sporadic follow-up, and missed opportunities to begin treatment due to the health care providers judgment and stigma, can lead to becoming stuck in the same cycle [2]. Ultimately, it is vital to determine a patient's full history. Displays of judgment that evoke a patient's sense of being stigmatized will more likely lead to an improper diagnosis and treatment by the healthcare team. If a treatment is not effective, then understanding the options to reassess and change the course of treatment become necessary. Opioid administration guidelines have been slowly changing since 2005 with the concept of 'not every increase in pain should be met with a higher dose of narcotics (opioids)' [3]. Further research into hormonal, dietary, and other natural or integrative methods of the treatment of pain is increasingly necessary, especially as the costs of opioid use for misdiagnosed pain become more widely known.

Today healthcare providers are working to lower opioid use in their own way, some in systemized fashion, while other just draw a line in their practice and hope that patients' pain improves, and/or that the patients get tired of asking for medication. But the use of opioids, especially, in pain management today is a complex

Pain and the treatment or management of pain is a widely debated subject. It is typically not a favorite topic of most providers; many feel they were not trained to care for the wide variety of pain complaints and some throw their hands up in frustration at the myriad of complaints they hear. Some providers have changed their office policy to include a blanket statement, "I do not prescribe narcotics." The reason for this policy, gleaned through many conversations with providers, is that they prefer to avoid the many 'headaches' from the 'drug seekers.' Case Study 1 illustrates this problem.

A patient arrives at the Emergency Department with no external presenting problems, but she describes her internal pain as, 'I feel like I am going to break apart.' She had undergone surgery 1 week prior, a straightforward laparoscopic cholecystectomy, but she is sure there is an infection or something worse inside. The staff in the Emergency Room see her often for her anxiety; they have other patients with 'true' emergencies in the rooms next door. Should she receive opioids for her pain? She and others like her struggle with feelings of anxiety, fear, pain and often come to the Emergency Department for relief. On a daily basis, patients with chronic pain feel their pain in a way that is difficult to express to others. Their previous experiences of anxiety, trauma, chronic disease, and previous treatment with opioids influence

anxiety, fear, and pain matrix in the prefrontal cortex and amygdala. This is influenced by neurotransmitters and glial cell activation, which can lead to pervasive inflammation and central sensitivity. It is paramount that hospitals utilize nonopioid and multi-modal treatments after surgeries to reduce opioid exposure of the brain. The exposure of the insula and the limbic area of the brain to morphine or hydromorphone begins the cascade of blocking endogenous opioid production.

**2. Current practices in pain treatment**

*Opioids - From Analgesic Use to Addiction*

landscape.

**Case Study 1**

their current situation.

**14**

A postoperative patient changed pharmacies shortly after surgery. He was able to receive the first 7 days of medication, but while the pharmacy was waiting for a phone call to complete his authorization, he did not have access to his regularly prescribed medication. This contributed to a pain crisis and he was hospitalized for 3 days. With his regular opioid medication dosage, the admission could have been prevented. The patient was not misusing his medication; he was affected by a ruling that was put in place to safeguard opioid medication from getting in to the hands of those who do not need a large quantity of opioid medication (from Ref. [3]).

Many state surgical organizations are taking notice of the overprescribing on the part of their members in the past. A not uncommon unintended consequence of this practice has been for post-operative patients, historically, to take a few oral pain relievers, and then the rest of the bottle of hydrocodone (Norco™, Vicodin) or oxycodone (Percocet™) sits in the medicine cupboard for many years. The result is that many household opioid supplies allow patients to self- and over-medicate in ways that "fly under the radar" of healthcare personnel. Case Study 3 is one such instance:

### **Case Study 3**

A patient arrived at the Emergency Room in clear distress from her new onset pneumonia. She was experiencing significant chest discomfort, and asked for pain medications since her hydrocodone with acetaminophen 7.5/325 mg was not working; the patient felt that something stronger was needed, and so insisted on a stronger dose. Emergency Room providers do not routinely administer opioids for pneumonia, so she left the hospital against medical advice, frustrated that her pain was not controlled. She eventually returned due to her worsening pneumonia symptoms, which resulted in hospitalization.

### **3. Factors that affect the experience of pain**

Ossipov et al. [4] found the experience of pain to be influenced by emotions and experiences. Painful experiences accompanied by intense emotions, such as wartime injuries, or co-occurring mental health disorders play a role in the body's own endogenous inhibitory system in heightening the pain perception.

Pain perception and modulation are important concepts to understand within pain management and its treatment, as in **Figure 1**.

The following is not an exhaustive list of some of the complexities of the experience of pain; they are offered to show that today's pain management provider must be something of a jack-of-all-trades in order to understand the nature and treatment of pain.


and these patients often need higher doses of medications to be able to

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing…*

• *An increasingly obese population has implications for pain management*. Obesity becomes a post-operative barrier to surgery due to lack of mobility. Physical therapy pain can be more intense and last longer if movement has been

The list of considerations entailed in understanding the nature of pain and subsequent pain management could go on. Patients with debilitating illnesses who have had to retire early may be less mobile and so more susceptible to pain—postoperative or other. Clinical observations reveal that back pain and spinal stenosis can leave a patient with weak proximal thigh muscles and the inability to walk more than 30–40 feet, while daily headaches can lead to the inability to leave the home for weeks at a time. Prolonged chronic pain and discomfort often leads to disability. Disability from pain is increasing. Clinically, patients become more and more deconditioned. They often ambulate or walk less, lose muscle mass, and may become discouraged and often depressed. Some eat lower-quality food, as in the case of a 50-year-old patient who told me that she orders from a mobile app at home and has her food delivered to her, since she cannot drive or stand to cook. Her diet is fast food almost exclusively. This leads to isolation and emotional 'sadness' as described by many patients. Many of the pain patients in my practice state, 'I want to be a good parent (or son, daughter, wife, husband), but I hurt too much.' The

As if the complexities of pain management just addressed were not enough, there are the important differences in types of pain, not just differences in patients. Patients with fibromyalgia, chronic fatigue, and small fiber neuropathy suffer from a category of pain known as central intractable pain (CIP)—a type of pain that does not respond to opioids and is, in fact, a type of pain for which the use of opioids has

Understanding CIP is vital for diagnosis, and for treatment modalities. Joshi [10] describes the etiology of CIP in terms of brain stimulation due to trauma or injury. NMDA and glutamate are released, and, due to glutamate excitability, glial cells are released. These glial cells are irritated and inflamed, and cytokines release cytotoxins. These cytotoxins are neurotoxins, are pervasive throughout the body, and cause damage to nerves from inflammation. Sensory nerve fibers are specifically targeted. It is important to stress here it is believed that the patient's subjective experience of events as emotionally traumatic in triggering this physiological

There are other variables that can compound and exacerbate this process. There are genes that have been found to be involved in the amplification of pain and may indicate an increased risk of chronic pain development [11]. In addition, there are environmental influences. Previous emotional trauma, sexual abuse, medical influenced trauma, previous stigma from the LGBTQ or other gender related or minority stress inducers has been thought to amplify pain perception. The Substance Abuse and Mental Health Services Administration (SAMSHA) have developed Trauma-informed care education for health care providers for these populations [12]. Treatment is typically a multi-faceted approach to minimize sensitization; there

response that results in cytotoxins' attack on sensory nerve fibers.

are a number of ways that this can be affected:

tolerate movement.

*DOI: http://dx.doi.org/10.5772/intechopen.85192*

difficult for a patient.

psychological and cognitive dysfunction persist.

**4. The missing link: central intractable pain**

been detrimental [8, 9].

**17**

surprisingly, that their needs are viewed as of secondary importance when they perceive that their sense of urgency is not matched by healthcare team.


*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing… DOI: http://dx.doi.org/10.5772/intechopen.85192*

and these patients often need higher doses of medications to be able to tolerate movement.

• *An increasingly obese population has implications for pain management*. Obesity becomes a post-operative barrier to surgery due to lack of mobility. Physical therapy pain can be more intense and last longer if movement has been difficult for a patient.

The list of considerations entailed in understanding the nature of pain and subsequent pain management could go on. Patients with debilitating illnesses who have had to retire early may be less mobile and so more susceptible to pain—postoperative or other. Clinical observations reveal that back pain and spinal stenosis can leave a patient with weak proximal thigh muscles and the inability to walk more than 30–40 feet, while daily headaches can lead to the inability to leave the home for weeks at a time. Prolonged chronic pain and discomfort often leads to disability.

Disability from pain is increasing. Clinically, patients become more and more deconditioned. They often ambulate or walk less, lose muscle mass, and may become discouraged and often depressed. Some eat lower-quality food, as in the case of a 50-year-old patient who told me that she orders from a mobile app at home and has her food delivered to her, since she cannot drive or stand to cook. Her diet is fast food almost exclusively. This leads to isolation and emotional 'sadness' as described by many patients. Many of the pain patients in my practice state, 'I want to be a good parent (or son, daughter, wife, husband), but I hurt too much.' The psychological and cognitive dysfunction persist.

### **4. The missing link: central intractable pain**

As if the complexities of pain management just addressed were not enough, there are the important differences in types of pain, not just differences in patients. Patients with fibromyalgia, chronic fatigue, and small fiber neuropathy suffer from a category of pain known as central intractable pain (CIP)—a type of pain that does not respond to opioids and is, in fact, a type of pain for which the use of opioids has been detrimental [8, 9].

Understanding CIP is vital for diagnosis, and for treatment modalities. Joshi [10] describes the etiology of CIP in terms of brain stimulation due to trauma or injury. NMDA and glutamate are released, and, due to glutamate excitability, glial cells are released. These glial cells are irritated and inflamed, and cytokines release cytotoxins. These cytotoxins are neurotoxins, are pervasive throughout the body, and cause damage to nerves from inflammation. Sensory nerve fibers are specifically targeted. It is important to stress here it is believed that the patient's subjective experience of events as emotionally traumatic in triggering this physiological response that results in cytotoxins' attack on sensory nerve fibers.

There are other variables that can compound and exacerbate this process. There are genes that have been found to be involved in the amplification of pain and may indicate an increased risk of chronic pain development [11]. In addition, there are environmental influences. Previous emotional trauma, sexual abuse, medical influenced trauma, previous stigma from the LGBTQ or other gender related or minority stress inducers has been thought to amplify pain perception. The Substance Abuse and Mental Health Services Administration (SAMSHA) have developed Trauma-informed care education for health care providers for these populations [12].

Treatment is typically a multi-faceted approach to minimize sensitization; there are a number of ways that this can be affected:

surprisingly, that their needs are viewed as of secondary importance when they perceive that their sense of urgency is not matched by healthcare team.

Rooms that generalize treatments rather than allow for individual treatments

• *Patient frustration can be high*. Maintaining the provider-patient relationship can be difficult if the non-opioid medications do not work, and the only thing that helps is the opioid pain relievers [6]. The real struggle comes when the opioids are ineffective or requests for more and more opioids occur, especially if a provider is not aware of other options for pain control or even the true diagnosis of the patient. This is exacerbated by the fact that if opioids are overused, the diagnostic picture can become clouded due to suspicion.

• *Patient expectations are based on past history*. Often, when a patient comes to the Emergency Room and has a history of being on chronic opioids, the opioids become the focus of the visit. The struggle begins: the patient feels they deserve more, since their home medications (including, sometimes, that leftover hydrocodone or oxycodone) do not work. For her part, the provider does not want to give opioids, given the growing awareness of opioid-related problems, especially now that providers receive scorecards with their opioid

• *Surgical delay can limit choices for the orthopedic patient*. Current guidelines for knee replacement are to 'proceed with total joint replacement after **all** other modalities have failed' [7]. This delay may increase the use of opioids since many patients struggle with limited mobility, and perhaps severe pain for many months or years, until they have qualified for the replacement.

Ironically, a predisposition to leap to opioids is often done in order to delay the surgery. Recovery is often delayed due to the muscle atrophy of older patients,

• *Patient pain care guidelines do not have individual complex patients in mind*. It is a constant challenge to maintain a targeted therapy for a patient and stay within the morphine milligrams guidelines as set by national and state guidelines. Some states have even prepared guidelines for Emergency

of pain [5].

*Factors influencing the pain experience [4].*

*Opioids - From Analgesic Use to Addiction*

**Figure 1.**

prescribing measured.

**16**


of individualized care plans by a Complex Care team has helped reduce

specific period of study.

**Case Study 4**

her family.

opioids.

1

**19**

the importance of recognizing CIP.

*DOI: http://dx.doi.org/10.5772/intechopen.85192*

readmissions by 36%.1 The goal is to assist the patient to find proper outpatient treatment, so that a readmission to the Emergency Room becomes less necessary. The goals of the care plans include providing appropriate symptom management, as well as reducing the opioids that are prescribed during the Emergency Room visit, and at discharge. Other techniques include giving a welcome letter to a patient that frequently uses the Emergency Room. The goals of the letter are to (1) alert patients to the program; (2) introduce the Complex Care team; (3) offer to help patients obtain a primary care physician; and in accordance with the Center for Disease Control Guidelines; (4) state clearly that we will not always treat their pain with opioids, but will use a multimodal approach when they present for treatment. These specific strategies have reduced the readmission rate by 60–70% during a more

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing…*

Identification and diagnosis is paramount to optimizing treatment strategies and symptom management. Patients who frequent the Emergency Room can be misunderstood with characteristics that are not always identified early in their pain treatment. This can place the patient at risk for over-medication syndromes, over-

Retrospectively, identification of complex patients who have symptoms that correlate to those identified as CIP has been ongoing. Recognizing CIP has resulted in revised treatment plans for patients. Case Study 4 describes one such instance of

A patient experienced a significant traumatic event when she was young. She developed low back pain and abdominal pain, although the imaging for both were not significant enough to pinpoint the cause for the pain. She had multiple medical procedures and work-ups, and because she complained of severe pain even after other medications, opioids were begun. Over the years, the dosages were increased, but they were not effective. The pain continued despite the subsequent overuse of the opioids. She eventually had

After being treated for opioid addiction, the patient was introduced to the concept of ketamine treatment for desensitization for central pain. After a series of ketamine infusions, the central sensitization subsided. The patient was able to use significantly less opioids, with much greater relief of the pain. She has now learned to identify the triggers of her pain exacerbations, and has been able to be active and care for

Informal conversations with colleagues at other institutions suggest that our suburban hospital is not the only facility to have concerns about patients similar to the one described above. Recognizing that many pain patients have a type of central sensitization—chronic pain that is out of control—can both reduce pain that is activated by a physical response to a past stressor—and the repeated exposure to

supratentorial pain can reduce reliance upon opioids and subsequent opioid-related addiction problems. Some of the implications found in the cases below include nonopioid pain management, the use of postoperative lidocaine, and desensitization with ketamine. This is consistent with the prevention of opioid exposure as the new

The case studies below represent how recognizing the role of CIP in

paradigm, and the need to implement innovative treatments.

Source: unpublished data from 2015 to 2017 (Delnor Hospital, Geneva, Illinois, USA).

utilization of the healthcare system, and developing central sensitization.

multiple admissions to the hospital without a cause for the pain identified.

	- Increase in cerebral blood flow
	- Resetting of the mu receptor
	- Reduction of hypersensitivity
	- Reversal, in some cases, of post-traumatic stress disorder (PTSD)
	- NMDA receptors mediation
	- It serves as a potent neuro-anti-inflammatory agent

Early identification of central pain syndromes prevents the central sensitization and brain reorganization. Functional MRIs show cortical reorganization: psychologic interaction with pain and stress that causes areas in the brain to become hyperactive to a stimulus, including brain mapping and biofeedback [16]. CIP, then, often has its origins in supratentorial factors, and failure to take these factors seriously can result in opioid overuse.

### **5. The multiple visit patient complex care program**

The hospital-based team approach to helping multiple-visit patients has been successful at my suburban hospital for the past 3 years. Recent data indicates the use

### *A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing… DOI: http://dx.doi.org/10.5772/intechopen.85192*

of individualized care plans by a Complex Care team has helped reduce readmissions by 36%.1 The goal is to assist the patient to find proper outpatient treatment, so that a readmission to the Emergency Room becomes less necessary. The goals of the care plans include providing appropriate symptom management, as well as reducing the opioids that are prescribed during the Emergency Room visit, and at discharge. Other techniques include giving a welcome letter to a patient that frequently uses the Emergency Room. The goals of the letter are to (1) alert patients to the program; (2) introduce the Complex Care team; (3) offer to help patients obtain a primary care physician; and in accordance with the Center for Disease Control Guidelines; (4) state clearly that we will not always treat their pain with opioids, but will use a multimodal approach when they present for treatment. These specific strategies have reduced the readmission rate by 60–70% during a more specific period of study.

Identification and diagnosis is paramount to optimizing treatment strategies and symptom management. Patients who frequent the Emergency Room can be misunderstood with characteristics that are not always identified early in their pain treatment. This can place the patient at risk for over-medication syndromes, overutilization of the healthcare system, and developing central sensitization.

Retrospectively, identification of complex patients who have symptoms that correlate to those identified as CIP has been ongoing. Recognizing CIP has resulted in revised treatment plans for patients. Case Study 4 describes one such instance of the importance of recognizing CIP.

### **Case Study 4**

1. Prevent the exposure to opioids.

*Opioids - From Analgesic Use to Addiction*

scores after surgery.

assist with pain control [15].

2. Minimize the wind up phenomena. Defined as stimulation of pain nerve fibers to the extent that the fibers are altered and produce neuropathic pain.

3. Setting the expectation for patients prior to painful experiences. Information and education of patients and providers has proven to lower patients' pain

4.The use of oral Naloxone™ has been on the rise in the recent past due to the research surrounding the stimulation of the midbrain periaqueductal grey (PAG) region. Outputs from the PAG to the medulla reduce pain by activating

5. Lidocaine has been used for over 50 years as a local anesthetic; now it is

and analgesic properties. Postoperative infusions at a low dose have effectively lowered opioid requirements, decreased post-operative nausea,

6.Hormone replacement has been shown to indicate that various hormones regulate the hypothalamic-pituitary-adrenal axis, which, when activated cause persistent pain. Multiple hormones are implicated here, including cortisol and pregnenolone. Dr. Forrest Tennant has developed a protocol for patients who have Ehlers Danlos syndrome and arachnoiditis, which replaces hormones to

7. Dr. Jay Joshi [10] has worked diligently to determine an appropriate plan for individual patients who struggle with CIP, using a treatment plan that relies on

• Reversal, in some cases, of post-traumatic stress disorder (PTSD)

Early identification of central pain syndromes prevents the central sensitization and brain reorganization. Functional MRIs show cortical reorganization: psychologic interaction with pain and stress that causes areas in the brain to become hyperactive to a stimulus, including brain mapping and biofeedback [16]. CIP, then, often has its origins in supratentorial factors, and failure to take these factors

The hospital-based team approach to helping multiple-visit patients has been successful at my suburban hospital for the past 3 years. Recent data indicates the use

• It serves as a potent neuro-anti-inflammatory agent

**5. The multiple visit patient complex care program**

assisting with less exposure to opioid medications due to its anti-inflammatory

an endogenous opioidergic pain inhibitory system [13].

and enhanced the return of bowel function [14].

ketamine, which has the following benefits:

• Increase in cerebral blood flow

• Resetting of the mu receptor

• Reduction of hypersensitivity

• NMDA receptors mediation

seriously can result in opioid overuse.

**18**

A patient experienced a significant traumatic event when she was young. She developed low back pain and abdominal pain, although the imaging for both were not significant enough to pinpoint the cause for the pain. She had multiple medical procedures and work-ups, and because she complained of severe pain even after other medications, opioids were begun. Over the years, the dosages were increased, but they were not effective. The pain continued despite the subsequent overuse of the opioids. She eventually had multiple admissions to the hospital without a cause for the pain identified.

After being treated for opioid addiction, the patient was introduced to the concept of ketamine treatment for desensitization for central pain. After a series of ketamine infusions, the central sensitization subsided. The patient was able to use significantly less opioids, with much greater relief of the pain. She has now learned to identify the triggers of her pain exacerbations, and has been able to be active and care for her family.

Informal conversations with colleagues at other institutions suggest that our suburban hospital is not the only facility to have concerns about patients similar to the one described above. Recognizing that many pain patients have a type of central sensitization—chronic pain that is out of control—can both reduce pain that is activated by a physical response to a past stressor—and the repeated exposure to opioids.

The case studies below represent how recognizing the role of CIP in supratentorial pain can reduce reliance upon opioids and subsequent opioid-related addiction problems. Some of the implications found in the cases below include nonopioid pain management, the use of postoperative lidocaine, and desensitization with ketamine. This is consistent with the prevention of opioid exposure as the new paradigm, and the need to implement innovative treatments.

<sup>1</sup> Source: unpublished data from 2015 to 2017 (Delnor Hospital, Geneva, Illinois, USA).

### **Case Study 5**

A patient with significant head pain sought diagnosis for her pain at multiple facilities without a definite diagnosis. All headache abortive efforts failed, and all multimodal management failed to relieve the pain. The patient was placed on intravenous meperidine and over the course of many years, the dosage was raised to a high dose. This was effective for a short time, but then the high dose began to fail in efficacy. Reinterpretation of her pain in terms of CIP etiology has resulted in conversations about stressors in her social life, and a reduction of opioids.

Activity can be the best treatment for most pain. Exercise and stretching of muscles, and desensitization of scar tissue leads to healing. Part of the CPMP is cognitive therapy, psychological, neurological, and pain education. It is clear that improving outcomes in chronic pain management occur when the patient under-

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing…*

The FDA and other research opportunities should be supported to continue to find more methods of pain blockade and prevention of pain at the site of surgery. Kaiser Permanente and other hospitals around the United States have been adopting the enhanced recovery after surgery (ERAS) concept. There is a full protocol of management of the patient, but the basic tenet is to block the pain to speed recovery

Lowering opioid exposure is paramount and should be supported and rewarded with funding and research grants. Health care and surgeries with minimal or no opioids are possible now, and need to be utilized immediately. Minimizing opioid exposure is the mandate at this time, there are available options presently, and more research dollars should be committed to new ways to block the perception of pain. Finally, patients should be educated about the options and choose hospitals and

Education of the next generation of providers needs to be clear in the direction and potential options for preventing disability and preventing overuse syndromes, early identification and the importance of prevention of the central sensitization and CIP.

The Northwestern Medicine Delnor Hospital Multiple Visit Complex Care Team

I acknowledge my mentor, Mary Lyons, and will always remember the strength

has offered immeasurable support for the growth of the program. They have supported the patients, the medical staff, and myself through the challenges of the

that came from our weekly west region collaboration. The years we worked in tandem were spectacular. I learned so very much from you and feel honored to have

I have truly appreciated Kim Czaruk, Director, who has supported the pain

I thank and respect the patients who struggle with pain and other debilitating symptoms themselves who have taught me invaluable lessons about listening and learning during my years in pain practice. I seek to pass on the non-text book wisdom they have taught me, and pass on the respect for pain management patients that I feel. I believe in thinking outside of the box, and never saying 'there is nothing

Thank you to my family, who have eaten cold food, washed my clothes, shopped for groceries, helped keep the house afloat, assisted with edits, and provided tech

support. We are on the same team, and I love each one for your support.

stands the influence the mind and the body play in pain perception.

providers who utilize the most up-to-date resources.

you as my esteemed colleague in pain management.

program and has been an encouragement daily.

with very little or no opioids.

*DOI: http://dx.doi.org/10.5772/intechopen.85192*

**Acknowledgements**

else I can do for your pain.'

No conflict of interest to declare.

**Conflict of interest**

**Thanks**

**21**

grass roots beginning of the endeavor.

### **Case Study 6**

A patient had a cervical spinal cord stimulator placed, but it failed almost immediately, worsening her pain. Struggles with anxiety and debility have contributed to a clinical diagnosis of depression. Treatment for depression has resulted in less frequent PTSD responses to an earlier-life trauma. As a result, her pain is not managed with less reliance on opioids.

### **Case Study 7**

A patient has progressive neuropathy, although the reason is unclear. Initially she presented with the inability to sit up long enough to go to her primary care physician's office, which suggested significant psychological overlay. Opioids were escalated, and her ability to sit comfortably and walk easily did improve. Care conferences ensued and biopsies, along with neurologic medication were used without improvement. Finally, the recognition that CIP might, at least in part, have had a role in the patient's symptoms resulted in fewer symptoms and a consequent reduction of opioids.

### **6. Conclusion and recommendations**

The management of pain by health care providers and pain specialists has a new contour: identify the patients with CIP in a timely manner, then identify treatments and methods to find sustained relief with limited or no use of opioids.

A patient's previous history of PTSD, anxiety (general anxiety disorder, postpartum depression, etc.), chronic pain, or substance use disorder matters when it comes to differential diagnoses. It is vital that health care providers realize the ramifications of co-existing psychological and neurologic impact when planning for surgery or other pain-producing procedures.

What might be routine and typical surgery/procedure from the perspective of a surgeon could be different to the brain, neurotransmitters, and the other aspects of a patient's neuroanatomy. It is crucial that patients' prior history be considered, and a plan put in place to assist the patient in coping. Pre-surgical education and planning, along with collaboration between anesthesia or social work colleagues can have a longterm positive effect. It may be beneficial to place a temporary nerve block, low dose lidocaine, or bupivacaine (either short acting or long-acting) in order to block the ascending nociceptors from sending the pain signal through the descending pain pathway. The future of pain management must be the prevention of pain pathway activation. This will lower the exposure to opioids and prevent future substance use disorder.

Of note, physical therapy is very beneficial to a large subset of patients. Specialized concepts have been developed by physiatrists' (also called physical medicine and rehabilitation specialists) to assist patients with chronic pain, known as an integrative comprehensive pain management program (CPMP). This program revealed significant improvement through the administration of a battery of observed functional tests (BOFT) to patients with chronic pain who were attending the CPMP [13].

### *A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing… DOI: http://dx.doi.org/10.5772/intechopen.85192*

Activity can be the best treatment for most pain. Exercise and stretching of muscles, and desensitization of scar tissue leads to healing. Part of the CPMP is cognitive therapy, psychological, neurological, and pain education. It is clear that improving outcomes in chronic pain management occur when the patient understands the influence the mind and the body play in pain perception.

The FDA and other research opportunities should be supported to continue to find more methods of pain blockade and prevention of pain at the site of surgery. Kaiser Permanente and other hospitals around the United States have been adopting the enhanced recovery after surgery (ERAS) concept. There is a full protocol of management of the patient, but the basic tenet is to block the pain to speed recovery with very little or no opioids.

Lowering opioid exposure is paramount and should be supported and rewarded with funding and research grants. Health care and surgeries with minimal or no opioids are possible now, and need to be utilized immediately. Minimizing opioid exposure is the mandate at this time, there are available options presently, and more research dollars should be committed to new ways to block the perception of pain. Finally, patients should be educated about the options and choose hospitals and providers who utilize the most up-to-date resources.

Education of the next generation of providers needs to be clear in the direction and potential options for preventing disability and preventing overuse syndromes, early identification and the importance of prevention of the central sensitization and CIP.

### **Acknowledgements**

**Case Study 5**

**Case Study 6**

**Case Study 7**

**20**

life, and a reduction of opioids.

*Opioids - From Analgesic Use to Addiction*

not managed with less reliance on opioids.

**6. Conclusion and recommendations**

surgery or other pain-producing procedures.

A patient with significant head pain sought diagnosis for her pain at multiple facilities without a definite diagnosis. All headache abortive efforts failed, and all multimodal management failed to relieve the pain. The patient was placed on intravenous meperidine and over the course of many years, the dosage was raised to a high dose. This was effective for a short time, but then the high dose began to fail in efficacy. Reinterpretation of her pain in terms of CIP etiology has resulted in conversations about stressors in her social

A patient had a cervical spinal cord stimulator placed, but it failed almost immediately, worsening her pain. Struggles with anxiety and debility have contributed to a clinical diagnosis of depression. Treatment for depression has resulted in less frequent PTSD responses to an earlier-life trauma. As a result, her pain is

A patient has progressive neuropathy, although the reason is unclear. Initially she presented with the inability to sit up long enough to go to her primary care physician's office, which suggested significant psychological overlay. Opioids were escalated, and her ability to sit comfortably and walk easily did improve. Care conferences ensued and biopsies, along with neurologic medication were used without improvement. Finally, the recognition that CIP might, at least in part, have had a role in the patient's

The management of pain by health care providers and pain specialists has a new contour: identify the patients with CIP in a timely manner, then identify treatments

A patient's previous history of PTSD, anxiety (general anxiety disorder, postpartum depression, etc.), chronic pain, or substance use disorder matters when it comes to differential diagnoses. It is vital that health care providers realize the ramifications of co-existing psychological and neurologic impact when planning for

What might be routine and typical surgery/procedure from the perspective of a surgeon could be different to the brain, neurotransmitters, and the other aspects of a patient's neuroanatomy. It is crucial that patients' prior history be considered, and a plan put in place to assist the patient in coping. Pre-surgical education and planning, along with collaboration between anesthesia or social work colleagues can have a longterm positive effect. It may be beneficial to place a temporary nerve block, low dose lidocaine, or bupivacaine (either short acting or long-acting) in order to block the ascending nociceptors from sending the pain signal through the descending pain pathway. The future of pain management must be the prevention of pain pathway activation. This will lower the exposure to opioids and prevent future substance use disorder. Of note, physical therapy is very beneficial to a large subset of patients. Specialized concepts have been developed by physiatrists' (also called physical medicine and rehabilitation specialists) to assist patients with chronic pain, known as an integrative comprehensive pain management program (CPMP). This program revealed significant improvement through the administration of a battery of observed functional tests (BOFT) to patients with chronic pain who were attending the CPMP [13].

symptoms resulted in fewer symptoms and a consequent reduction of opioids.

and methods to find sustained relief with limited or no use of opioids.

The Northwestern Medicine Delnor Hospital Multiple Visit Complex Care Team has offered immeasurable support for the growth of the program. They have supported the patients, the medical staff, and myself through the challenges of the grass roots beginning of the endeavor.

I acknowledge my mentor, Mary Lyons, and will always remember the strength that came from our weekly west region collaboration. The years we worked in tandem were spectacular. I learned so very much from you and feel honored to have you as my esteemed colleague in pain management.

I have truly appreciated Kim Czaruk, Director, who has supported the pain program and has been an encouragement daily.

I thank and respect the patients who struggle with pain and other debilitating symptoms themselves who have taught me invaluable lessons about listening and learning during my years in pain practice. I seek to pass on the non-text book wisdom they have taught me, and pass on the respect for pain management patients that I feel. I believe in thinking outside of the box, and never saying 'there is nothing else I can do for your pain.'

### **Conflict of interest**

No conflict of interest to declare.

### **Thanks**

Thank you to my family, who have eaten cold food, washed my clothes, shopped for groceries, helped keep the house afloat, assisted with edits, and provided tech support. We are on the same team, and I love each one for your support.

*Opioids - From Analgesic Use to Addiction*

**References**

[1] Gaskin DJ, Richard P. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Appendix C: The economic costs of pain in the United States. In: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.

*DOI: http://dx.doi.org/10.5772/intechopen.85192*

Emergency Department and Immediate Care Centers. 2018. Available from: https://www.team-iha.org/files/nongated/quality/opioid-guidelineslongversion.aspx [Accessed: 20

[9] Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States. MMWR—Recommendations and Reports. 2016;**65**(RR-1):1-49. DOI: 10.15585/mmwr.rr6501e1 [Accessed: 21

[10] Joshi J. Chronic Pain Advocacy and Consulting Paper presented to the Midwest Pain Treatment and Education Expo. Chicago, Illinois. 2016. Available from: https://www.youtube.com/watch?

v=QshZ\_unVDQQ [Accessed: 20

[11] Foulkes T, Wood JN. Pain genes. PLoS Genetics. 2008;**4**(7):e1000086. DOI: https://doi.org/10.1371/journal. pgen.1000086 [Accessed: 20 September

[12] The Substance Abuse and Mental Health Services Administration. n.d. TIP

[14] Ventham N, Kennedy E. Efficacy of intravenous lidocaine for postoperative analgesia following laparoscopic

surgery: A meta-analysis. World Journal

[15] Tennant F, Lichota L. Testosterone replacement in chronic pain patients. Practical Pain Management. 2010;**10**(6):

of Surgery. 2015;**39**:220-2234

12-15. www.foresttennant.com [Accessed: 15 September 2018]

57, Trauma informed care (TIC)

[13] Oken J, Schwarz L, Brady S. Outcomes in an interdisciplinary comprehensive pain management program. In: Poster Presented to the 41st Midwest Pain Society Scientific Meeting; Chicago, Illinois. 2017

September 2018]

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing…*

September 2018]

September 2018]

2018]

nlm.nih.gov/books/NBK92521/

DOI: 10.1007/s11414-010-9227-6

York: Bloomsbury Press; 2015

3779. DOI: 10.1172/JC143766

30 September 2018]

**27**(10):38-49

**23**

[3] Quinones S. Dreamland: The True Tale of America's Opioid Epidemic. New

[4] Ossipov M, Dussor G, Porreca F. Central modulation of pain. The Journal of Clinical Investigation. 2010;**120**(11):

[5] Joseph A. CVS Tightens Restrictions on Opioid Prescriptions in Bid to Stanch Epidemic. 2017. Available from: https:// www.statnews.com/2017/09/21/cvsopioid-prescription-limits/ [Accessed:

[6] Hill MV, ML MM, Stucke RS, Barth RJ Jr. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Annals of Surgery. 2017;**265**(4):709-714

[7] Schneiderhan J, Orizondo C. Chronic pain how to approach these 3 common conditions. Clinical Reviews. 2017;

[8] Illinois Health and Hospital Association. Opioid Prescribing Guidelines for Patients in the

[2] Booth BM, Walton MA, Barry KL, Cunningham RM, Chermack ST, Blow FC. Substance use, depression and mental health functioning in patients seeking acute medical care in an innercity ED. The Journal of Behavioral Health Services & Research. 2011;**38**(3):358-372.

### **Author details**

Pamela Bolyanatz Northwestern Medicine Delnor Hospital, Geneva, Illinois, USA

\*Address all correspondence to: pamela.bolyanatz@nm.org

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*A New Paradigm: Prevention of Central Sensitization in Pain Management through Minimizing… DOI: http://dx.doi.org/10.5772/intechopen.85192*

### **References**

[1] Gaskin DJ, Richard P. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Appendix C: The economic costs of pain in the United States. In: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi. nlm.nih.gov/books/NBK92521/

[2] Booth BM, Walton MA, Barry KL, Cunningham RM, Chermack ST, Blow FC. Substance use, depression and mental health functioning in patients seeking acute medical care in an innercity ED. The Journal of Behavioral Health Services & Research. 2011;**38**(3):358-372. DOI: 10.1007/s11414-010-9227-6

[3] Quinones S. Dreamland: The True Tale of America's Opioid Epidemic. New York: Bloomsbury Press; 2015

[4] Ossipov M, Dussor G, Porreca F. Central modulation of pain. The Journal of Clinical Investigation. 2010;**120**(11): 3779. DOI: 10.1172/JC143766

[5] Joseph A. CVS Tightens Restrictions on Opioid Prescriptions in Bid to Stanch Epidemic. 2017. Available from: https:// www.statnews.com/2017/09/21/cvsopioid-prescription-limits/ [Accessed: 30 September 2018]

[6] Hill MV, ML MM, Stucke RS, Barth RJ Jr. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Annals of Surgery. 2017;**265**(4):709-714

[7] Schneiderhan J, Orizondo C. Chronic pain how to approach these 3 common conditions. Clinical Reviews. 2017; **27**(10):38-49

[8] Illinois Health and Hospital Association. Opioid Prescribing Guidelines for Patients in the

Emergency Department and Immediate Care Centers. 2018. Available from: https://www.team-iha.org/files/nongated/quality/opioid-guidelineslongversion.aspx [Accessed: 20 September 2018]

[9] Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States. MMWR—Recommendations and Reports. 2016;**65**(RR-1):1-49. DOI: 10.15585/mmwr.rr6501e1 [Accessed: 21 September 2018]

[10] Joshi J. Chronic Pain Advocacy and Consulting Paper presented to the Midwest Pain Treatment and Education Expo. Chicago, Illinois. 2016. Available from: https://www.youtube.com/watch? v=QshZ\_unVDQQ [Accessed: 20 September 2018]

[11] Foulkes T, Wood JN. Pain genes. PLoS Genetics. 2008;**4**(7):e1000086. DOI: https://doi.org/10.1371/journal. pgen.1000086 [Accessed: 20 September 2018]

[12] The Substance Abuse and Mental Health Services Administration. n.d. TIP 57, Trauma informed care (TIC)

[13] Oken J, Schwarz L, Brady S. Outcomes in an interdisciplinary comprehensive pain management program. In: Poster Presented to the 41st Midwest Pain Society Scientific Meeting; Chicago, Illinois. 2017

[14] Ventham N, Kennedy E. Efficacy of intravenous lidocaine for postoperative analgesia following laparoscopic surgery: A meta-analysis. World Journal of Surgery. 2015;**39**:220-2234

[15] Tennant F, Lichota L. Testosterone replacement in chronic pain patients. Practical Pain Management. 2010;**10**(6): 12-15. www.foresttennant.com [Accessed: 15 September 2018]

**Author details**

Pamela Bolyanatz

**22**

Northwestern Medicine Delnor Hospital, Geneva, Illinois, USA

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: pamela.bolyanatz@nm.org

provided the original work is properly cited.

*Opioids - From Analgesic Use to Addiction*

[16] Amen D. The Most Important Lesson From 83,000 Brain Scans; TED Talk. 2013. Available from: https:// www.youtube.com/watch?v=esPRsTlmw8 [Accessed: 20 September 2018]

**25**

**Chapter 3**

**Abstract**

**1. Introduction**

uses of morphine.

**2. Dyspnoea**

**2.1 Introduction**

*Shrenik Ostwal*

Other Uses of Morphine

**Keywords:** morphine, dyspnoea, mucositis, chronic cough,

opioid substitution therapy (OST), diarrhea

incomplete exhalation or feeling of suffocation.

Worldwide many different strong opioids and their formulations are available to control pain. Of which, morphine is considered as global opioid of choice and is widely used to control moderate to severe pain. The World Health Organization (WHO) has recommended morphine as one of the essential drug. Apart from analgesic use, research has proven its effectiveness for relief and treatment of various debilitating and distressing conditions like breathlessness, mucositis (oral and vaginal) and cough. However, its role in diarrhea and opioid substitution therapy (OST) is still nonconfirmatory. This chapter illustrates all available literature supporting effectiveness of morphine in above conditions and its impact on quality of life.

Preparations of the opium poppy *Papaver somniferum* have been used for many hundreds of years to relieve pain. Morphine remains as the gold standard for management of moderate to severe cancer pain. It has a five ringed structure with a characteristic T-shaped three dimensional form essential for activation of the opioid receptor. Due to its strong affinity to mu receptors and action similar to endorphins, i.e., natural pain killers, morphine has been widely used globally. Apart from its analgesic action, it can be used widely for symptomatic relief of other distressing and debilitating conditions. This chapter depicts all available literature for various other

Dyspnoea, also termed as breathlessness, is a common and prevalent source of discomfort in patients with advanced cancer and non-cancer life limiting illnesses. Most people describe it as an uncomfortable sensation or increased work of breathing in terms of air hunger, increased effort, chest tightness, rapid breathing,

The American Thoracic Society defined dyspnoea as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity" [1]. This definition highlights key areas where dyspnoea can be measured, suggesting that dyspnoea is not merely a single sensation but a shared experience with physical and affective components. This is similar to concept of

## **Chapter 3** Other Uses of Morphine

*Shrenik Ostwal*

### **Abstract**

[16] Amen D. The Most Important Lesson From 83,000 Brain Scans; TED Talk. 2013. Available from: https:// www.youtube.com/watch?v=esPRsTlmw8 [Accessed: 20 September 2018]

*Opioids - From Analgesic Use to Addiction*

**24**

Worldwide many different strong opioids and their formulations are available to control pain. Of which, morphine is considered as global opioid of choice and is widely used to control moderate to severe pain. The World Health Organization (WHO) has recommended morphine as one of the essential drug. Apart from analgesic use, research has proven its effectiveness for relief and treatment of various debilitating and distressing conditions like breathlessness, mucositis (oral and vaginal) and cough. However, its role in diarrhea and opioid substitution therapy (OST) is still nonconfirmatory. This chapter illustrates all available literature supporting effectiveness of morphine in above conditions and its impact on quality of life.

**Keywords:** morphine, dyspnoea, mucositis, chronic cough, opioid substitution therapy (OST), diarrhea

### **1. Introduction**

Preparations of the opium poppy *Papaver somniferum* have been used for many hundreds of years to relieve pain. Morphine remains as the gold standard for management of moderate to severe cancer pain. It has a five ringed structure with a characteristic T-shaped three dimensional form essential for activation of the opioid receptor.

Due to its strong affinity to mu receptors and action similar to endorphins, i.e., natural pain killers, morphine has been widely used globally. Apart from its analgesic action, it can be used widely for symptomatic relief of other distressing and debilitating conditions. This chapter depicts all available literature for various other uses of morphine.

### **2. Dyspnoea**

### **2.1 Introduction**

Dyspnoea, also termed as breathlessness, is a common and prevalent source of discomfort in patients with advanced cancer and non-cancer life limiting illnesses. Most people describe it as an uncomfortable sensation or increased work of breathing in terms of air hunger, increased effort, chest tightness, rapid breathing, incomplete exhalation or feeling of suffocation.

The American Thoracic Society defined dyspnoea as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity" [1]. This definition highlights key areas where dyspnoea can be measured, suggesting that dyspnoea is not merely a single sensation but a shared experience with physical and affective components. This is similar to concept of

total pain or total suffering which constitutes other domains like psychological, social, spiritual and environmental.

The prevalence of dyspnoea varies according to disease primary site and stage of illness. Studies by Muers and Round [2]; Smith et al. [3] reported prevalence of dyspnoea in 75–87% patients with primary lung cancer. While, a systematic review by Solano et al. [4] reported dyspnoea prevalence of: 90–95% in patients with chronic obstructive pulmonary disease (COPD), 60–88% in patients with heart disease, 11–62% in patients with AIDS and 11–62% in patients with renal disease. COPD and chronic heart failure (CHF) constitutes major non-cancer causes of dyspnoea in patients [5, 6].

Dyspnoea due to its prevalence and associated suffering poses a significant burden to patients and caregivers, hence severely affecting quality of life.

### **2.2 Pathophysiology of dyspnoea**

Normally during unconscious activity, respiration is managed by clusters of neurons in the medulla. They receive afferent input from several types of mechanoreceptors in respiratory muscles, airways, and lung parenchyma and chemoreceptors in aortic and carotid bodies and the medulla. Motor commands from the medulla or motor cortex by means of the medulla descend to respiratory muscles through efferent motor neurons [7, 8].

Differential diagnosis for dyspnoea in advanced cancer can be: (**Table 1**).

### **2.3 Opioids in breathlessness**

The primary site of action of opioids in breathlessness is through medulla oblongata, although various mechanisms may be involved on effect on perception of breathlessness. **Box 1** suggests various mechanisms by which morphine acts on breathlessness [1].

• Analgesia—reduction of pain induced respiratory drive.


### **Box 1.**

*Mechanism by which morphine reduces perception of breathlessness. Source: Adapted from American Thoracic Society guidelines on dyspnoea 2012.*

A study by Mahler et al. [9] in 2009 demonstrated threefold increase in beta endorphin levels in 17 COPD patients when compared from rest to end exercise. Patients were randomized to receive either normal saline or 10 mg of intravenous naloxone. Authors found significantly higher peak ratings and regression slope of breathlessness with naloxone as compared to normal saline. This study high-lighten role of endogenous opioids in dyspnoea modification in COPD patients.

Research has demonstrated role of oral morphine in breathlessness. However dosing schedule varies according to underlying condition. **Box 2** depicts morphine dosing recommendations for breathlessness [10]:

**27**

**Table 1.**

**Box 2.**

*Causes of dyspnoea.*

*Other Uses of Morphine*

effective dose is found.

*managing breathlessness in palliative care.*

condition.

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

• Prescribe laxatives and other supportive medications.

• Consider 1/6th of regular dose prn for episodic breathlessness.

*2.3.1 Morphine for breathlessness in cancer patients*

There is good evidence for role of opioids in breathlessness [1, 5, 11–20]. Most of studies illustrated beneficial effect of morphine in breathlessness in cancer patients. Out of eight studies which evaluated effect of morphine in cancer related dyspnoea, seven were randomized controlled, double blind trials [21]. Another study by Clemens et al. [22], a non-randomized prospective study in advanced terminal cancer patients with dyspnoea, reported beneficial effect of morphine in reducing intensity of dyspnoea when compared with oxygen. While, Charles et al. [23] also reported similar and rapid improvement in breathlessness with use of nebulised hydromorphone. Studies by Bruera et al. [15] and Mazocato et al. [24] compared role of subcutaneous morphine with placebo in patients with primary lung cancer or lung metastases, showing a significant decrease in breathlessness intensity on visual analogue scale (VAS) after 45 min of intervention when treated with morphine. This was supported by a meta-analysis by Ben-Aharon et al. [10] in patients with cancer related dyspnoea. Authors found positive effect of opioids in reducing breathlessness. Another two studies by Davis et al. (1996) and Grimbert et al. [25] reported no significant improvement in VAS scores even after 60 min of intervention with nebulized morphine when compared with placebo, i.e., nebulised saline. In one study Bruera et al. [15] compared effect of subcutaneous morphine with nebulised

**Malignant causes Non-malignant causes** Lung cancer/metastases to lung COPD/interstitial lung disease

• Opioids should be started when disabling dyspnoea persists despite maximal Management of underlying

• Titrate morphine dose (up to 25–50% of dose for continued mild to moderate dyspnoea; and by up to 50–100% of dose for continued moderate to severe dyspnoea) every weekly over 4 weeks until lowest

*Morphine dosing recommendations for breathlessness. Source: Adapted and developed from best practice for* 

• Check for renal, hepatic, pulmonary function, current and past opioid use.

• Adopt policy of "Start Low and Go Slow" while titrating morphine dosage.

• Start with 2.5–5 mg/4 h. PO or 1–2.5 mg/4 h. SC of morphine in opioid naive patients. • For patients already prescribed morphine for pain, increase regular dose by 25–30%. • Consider long acting twice daily morphine dosing in patients with stable regular dose.

Superior vena caval obstruction Congestive heart failure

Pulmonary edema Motor neuron diseases Major airway obstruction Muscular dystrophy

Radiation induced pulmonary fibrosis Anxiety/panic attacks

Pleural effusion/pericardial effusion/ascites Bronchiectasis

Pulmonary embolism Arrhythmias

Lymphangitis carcinomatosis Anaemia Chest wall infiltration Acidosis

<sup>•</sup> Anxiolytic effects.


### **Box 2.**

*Opioids - From Analgesic Use to Addiction*

social, spiritual and environmental.

dyspnoea in patients [5, 6].

**2.2 Pathophysiology of dyspnoea**

efferent motor neurons [7, 8].

**2.3 Opioids in breathlessness**

• Analgesia—reduction of pain induced respiratory drive.

• Cortical sedation (suppression of respiratory awareness).

• Vasodilatation and improved cardiac functions.

*Society guidelines on dyspnoea 2012.*

• Alteration of neurotransmission within medullary respiratory center. • Reduce central sensitivity and response to hypercarbia or hypoxia.

• Decreased metabolic rate and ventilatory requirements—decrease in O2 consumption.

breathlessness [1].

• Anxiolytic effects. • Reduce minute ventilation.

total pain or total suffering which constitutes other domains like psychological,

The prevalence of dyspnoea varies according to disease primary site and stage of illness. Studies by Muers and Round [2]; Smith et al. [3] reported prevalence of dyspnoea in 75–87% patients with primary lung cancer. While, a systematic review by Solano et al. [4] reported dyspnoea prevalence of: 90–95% in patients with chronic obstructive pulmonary disease (COPD), 60–88% in patients with heart disease, 11–62% in patients with AIDS and 11–62% in patients with renal disease. COPD and chronic heart failure (CHF) constitutes major non-cancer causes of

Dyspnoea due to its prevalence and associated suffering poses a significant

Differential diagnosis for dyspnoea in advanced cancer can be: (**Table 1**).

The primary site of action of opioids in breathlessness is through medulla oblongata, although various mechanisms may be involved on effect on perception of breathlessness. **Box 1** suggests various mechanisms by which morphine acts on

A study by Mahler et al. [9] in 2009 demonstrated threefold increase in beta endorphin levels in 17 COPD patients when compared from rest to end exercise. Patients were randomized to receive either normal saline or 10 mg of intravenous naloxone. Authors found significantly higher peak ratings and regression slope of breathlessness with naloxone as compared to normal saline. This study high-lighten

*Mechanism by which morphine reduces perception of breathlessness. Source: Adapted from American Thoracic* 

Research has demonstrated role of oral morphine in breathlessness. However dosing schedule varies according to underlying condition. **Box 2** depicts morphine

role of endogenous opioids in dyspnoea modification in COPD patients.

dosing recommendations for breathlessness [10]:

Normally during unconscious activity, respiration is managed by clusters of neurons in the medulla. They receive afferent input from several types of mechanoreceptors in respiratory muscles, airways, and lung parenchyma and chemoreceptors in aortic and carotid bodies and the medulla. Motor commands from the medulla or motor cortex by means of the medulla descend to respiratory muscles through

burden to patients and caregivers, hence severely affecting quality of life.

**26**

**Box 1.**

*Morphine dosing recommendations for breathlessness. Source: Adapted and developed from best practice for managing breathlessness in palliative care.*


### **Table 1.**

*Causes of dyspnoea.*

### *2.3.1 Morphine for breathlessness in cancer patients*

There is good evidence for role of opioids in breathlessness [1, 5, 11–20]. Most of studies illustrated beneficial effect of morphine in breathlessness in cancer patients. Out of eight studies which evaluated effect of morphine in cancer related dyspnoea, seven were randomized controlled, double blind trials [21]. Another study by Clemens et al. [22], a non-randomized prospective study in advanced terminal cancer patients with dyspnoea, reported beneficial effect of morphine in reducing intensity of dyspnoea when compared with oxygen. While, Charles et al. [23] also reported similar and rapid improvement in breathlessness with use of nebulised hydromorphone. Studies by Bruera et al. [15] and Mazocato et al. [24] compared role of subcutaneous morphine with placebo in patients with primary lung cancer or lung metastases, showing a significant decrease in breathlessness intensity on visual analogue scale (VAS) after 45 min of intervention when treated with morphine. This was supported by a meta-analysis by Ben-Aharon et al. [10] in patients with cancer related dyspnoea. Authors found positive effect of opioids in reducing breathlessness.

Another two studies by Davis et al. (1996) and Grimbert et al. [25] reported no significant improvement in VAS scores even after 60 min of intervention with nebulized morphine when compared with placebo, i.e., nebulised saline. In one study Bruera et al. [15] compared effect of subcutaneous morphine with nebulised morphine in lung primary patients, reporting no significant difference in dyspnoea intensity. However, this study reported patient's preference with nebulised morphine. Lastly, Allard et al. [26] found no significant differences in VAS score with 25 or 50% increments in morphine dosages.

### *2.3.2 Morphine for breathlessness in COPD patients*

A systemic review and meta-analysis by Jennings et al., comparing opioids with placebo for the treatment of dyspnoea [21] showed out of 18 randomized controlled trials (RCT) involved, nine trials reported patients receiving either oral opioids (*n* = 8) or subcutaneous morphine (*n* = 1). Such patients experienced significant beneficial effect with parenteral opioids on reducing dyspnoea when compared with placebo (meanΔ: –0.40; CI: −0.32 to −0.17). However, exercise was used as provoking stimulus to dyspnoea in eight of these nine studies, whereas only one study could examine patients with dyspnoea at rest.

Another randomized, double blind, placebo-controlled crossover trial by Abernethy et al. [27] compared 4 days of 20 mg oral sustained-release morphine with 4 days of oral placebo. Thirty-eight (87.5%) participants who were opioid naive and had dyspnoea at rest in spite of optimal therapy for their underlying condition (mainly patients with COPD) completed the trial. Patients on morphine experienced significant improvements (i.e., less dyspnoea and improved sleep) on VAS scale. Hence, authors concluded that "sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting."

### *2.3.3 Morphine for breathlessness in heart failure patients*

Only few published studies have demonstrated positive outcomes with use of morphine in CHF related dyspnoea. In a pilot study by Johnson et al. [28] aimed to measure effect of oral morphine on breathlessness in patients with CHF, authors found a significant decrease in median breathlessness in those who received 5 mg of oral morphine four times a day (*p* = 0.022), whereas no change was observed in patients treated with placebo.

Oxberry et al. [29] conducted a crossover RCT on 35 patients diagnosed with CHF (New York Heart Association Grade III–IV) comparing 4 days of morphine (5 mg four times daily), oxycodone (2.5 mg four times daily) and placebo followed by a washout period of 3 days. Patients were followed up for 3 months. Authors found a significant improvement in composite breathlessness in opioid group as compared to placebo (*p* = 0.017). However they did not find any statistically significant difference in breathlessness improvement in either intervention group. Hence, authors concluded need for long term trials to establish effectiveness of opioids.

Before stating opioids for dyspnoea in CHF patients, all possible etio-pathological causes should be taken into consideration. Non-pharmacological treatment options salt and fluid restriction, diet modification, appropriate exercise training and weight reduction strategies, etc., should be used first. Pharmacological therapy with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta blockers, diuretics, digoxin and implant devices should be optimally considered. Other possible causes like anaemia and pleural effusion should be taken care of.

### *2.3.4 Morphine for breathlessness in other conditions*

A recent double blind study by Shohrati et al. [30] on 40 patients presented with dyspnoea due to mustard gas induced bronchiolitis obliterans reported

**29**

*Other Uses of Morphine*

overall quality of life.

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

by Cochrane review by Polosa et al. [33].

**3. Role of morphine in mucositis**

**3.1 Pathophysiology of mucositis**

1.Stage of initiation of tissue injury

4.Stage of ulceration and inflammation

Stages involved are [35]:

messenger signals

3.Stage of amplification

**3.2 Morphine and oral mucositis**

5.Stage of healing

intensity at 120 min after morphine administration.

cycles while gastrointestinal (GI) mucositis in 7% cycles.

effectiveness of nebulised morphine (1 mg diluted in 4 cc normal saline). Patients experienced improvements in dyspnoea VAS score, cough, night time awakenings both due to dyspnoea and cough, heart rate, respiratory rate and

A phase I clinical trial on six patients with interstitial lung disease (ILD) by Matsuda et al. [31] comparing two different doses of subcutaneous morphine injection demonstrated a tolerable dose of 2 mg to alleviate dyspnoea. However due to small sample size, results could not be reciprocated to general population and need for larger trials were recommended. On the other hand, Harris-Eze et al. [32] does not found any significant difference in exercise capacity and dyspnoea score in ILD patients treated with either 2.5 or 5 mg of nebulised morphine. This was supported

A single arm study of six patients with terminal amyotrophic lateral sclerosis (ALS) by Clemens et al. [22] showed effectiveness of morphine in reducing dyspnoea. Authors found a significant difference in respiratory rate and dyspnoea

Mucositis refers to erythematous, erosive and ulcerative lesion of mucosa observed in patients with cancer treated with chemotherapy and/or radiotherapy to fields involving areas of body. Accordingly it may involve oral cavity, gastrointestinal tract, vaginal mucosa or other areas. Hence, manifesting as burning pain in mouth, diarrhea, vaginitis, etc. Elting et al. [34] observed chemotherapy-induced mucositis in 303 out of 599 patients (51%). Oral mucositis was developed in 22%

The five-stage model depicts various steps involved in pathogenesis of mucositis.

2.Stage of signaling through up regulation of inflammation *via* generation of

Oral mucositis poses a significant source of pain and distress to patients receiving chemotherapy or radiotherapy to head and neck area. It often manifests as burning pain, ulcers, erythematous lesions in mouth complicated by secondary infections—bacterial/fungal/viral. It significantly affects nutritional intake, oral hygiene and overall quality of life. Infections associated with oral mucositis may pose life-threatening conditions. Adequate oral hygiene and treatment of underly-

ing cause helps to relieve symptoms and distress in patients [36, 37].

*Opioids - From Analgesic Use to Addiction*

or 50% increments in morphine dosages.

*2.3.2 Morphine for breathlessness in COPD patients*

study could examine patients with dyspnoea at rest.

*2.3.3 Morphine for breathlessness in heart failure patients*

*2.3.4 Morphine for breathlessness in other conditions*

the community setting."

patients treated with placebo.

morphine in lung primary patients, reporting no significant difference in dyspnoea intensity. However, this study reported patient's preference with nebulised morphine. Lastly, Allard et al. [26] found no significant differences in VAS score with 25

A systemic review and meta-analysis by Jennings et al., comparing opioids with placebo for the treatment of dyspnoea [21] showed out of 18 randomized controlled trials (RCT) involved, nine trials reported patients receiving either oral opioids (*n* = 8) or subcutaneous morphine (*n* = 1). Such patients experienced significant beneficial effect with parenteral opioids on reducing dyspnoea when compared with placebo (meanΔ: –0.40; CI: −0.32 to −0.17). However, exercise was used as provoking stimulus to dyspnoea in eight of these nine studies, whereas only one

Another randomized, double blind, placebo-controlled crossover trial by Abernethy et al. [27] compared 4 days of 20 mg oral sustained-release morphine with 4 days of oral placebo. Thirty-eight (87.5%) participants who were opioid naive and had dyspnoea at rest in spite of optimal therapy for their underlying condition (mainly patients with COPD) completed the trial. Patients on morphine experienced significant improvements (i.e., less dyspnoea and improved sleep) on VAS scale. Hence, authors concluded that "sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in

Only few published studies have demonstrated positive outcomes with use of morphine in CHF related dyspnoea. In a pilot study by Johnson et al. [28] aimed to measure effect of oral morphine on breathlessness in patients with CHF, authors found a significant decrease in median breathlessness in those who received 5 mg of oral morphine four times a day (*p* = 0.022), whereas no change was observed in

Oxberry et al. [29] conducted a crossover RCT on 35 patients diagnosed with CHF (New York Heart Association Grade III–IV) comparing 4 days of morphine (5 mg four times daily), oxycodone (2.5 mg four times daily) and placebo followed by a washout period of 3 days. Patients were followed up for 3 months. Authors found a significant improvement in composite breathlessness in opioid group as compared to placebo (*p* = 0.017). However they did not find any statistically significant difference in breathlessness improvement in either intervention group. Hence, authors concluded need for long term trials to establish effectiveness of opioids.

Before stating opioids for dyspnoea in CHF patients, all possible etio-pathological causes should be taken into consideration. Non-pharmacological treatment options salt and fluid restriction, diet modification, appropriate exercise training and weight reduction strategies, etc., should be used first. Pharmacological therapy with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta blockers, diuretics, digoxin and implant devices should be optimally considered. Other possible causes like anaemia and pleural effusion should be taken care of.

A recent double blind study by Shohrati et al. [30] on 40 patients presented with dyspnoea due to mustard gas induced bronchiolitis obliterans reported

**28**

effectiveness of nebulised morphine (1 mg diluted in 4 cc normal saline). Patients experienced improvements in dyspnoea VAS score, cough, night time awakenings both due to dyspnoea and cough, heart rate, respiratory rate and overall quality of life.

A phase I clinical trial on six patients with interstitial lung disease (ILD) by Matsuda et al. [31] comparing two different doses of subcutaneous morphine injection demonstrated a tolerable dose of 2 mg to alleviate dyspnoea. However due to small sample size, results could not be reciprocated to general population and need for larger trials were recommended. On the other hand, Harris-Eze et al. [32] does not found any significant difference in exercise capacity and dyspnoea score in ILD patients treated with either 2.5 or 5 mg of nebulised morphine. This was supported by Cochrane review by Polosa et al. [33].

A single arm study of six patients with terminal amyotrophic lateral sclerosis (ALS) by Clemens et al. [22] showed effectiveness of morphine in reducing dyspnoea. Authors found a significant difference in respiratory rate and dyspnoea intensity at 120 min after morphine administration.

### **3. Role of morphine in mucositis**

Mucositis refers to erythematous, erosive and ulcerative lesion of mucosa observed in patients with cancer treated with chemotherapy and/or radiotherapy to fields involving areas of body. Accordingly it may involve oral cavity, gastrointestinal tract, vaginal mucosa or other areas. Hence, manifesting as burning pain in mouth, diarrhea, vaginitis, etc. Elting et al. [34] observed chemotherapy-induced mucositis in 303 out of 599 patients (51%). Oral mucositis was developed in 22% cycles while gastrointestinal (GI) mucositis in 7% cycles.

### **3.1 Pathophysiology of mucositis**

The five-stage model depicts various steps involved in pathogenesis of mucositis. Stages involved are [35]:


### **3.2 Morphine and oral mucositis**

Oral mucositis poses a significant source of pain and distress to patients receiving chemotherapy or radiotherapy to head and neck area. It often manifests as burning pain, ulcers, erythematous lesions in mouth complicated by secondary infections—bacterial/fungal/viral. It significantly affects nutritional intake, oral hygiene and overall quality of life. Infections associated with oral mucositis may pose life-threatening conditions. Adequate oral hygiene and treatment of underlying cause helps to relieve symptoms and distress in patients [36, 37].

Various combination of local measures helps to take care of mucositis-related complications. Research has shown effectiveness of morphine gargles either alone (morphine rinse) or in combination with antacid, lignocaine viscous and dextromethorphan (magic mouth wash), in relieving pain and symptoms related to mucositis. A mini review by Dutta et al. [38] compared six studies using morphine as oral rinse. All studies showed satisfactory result in terms of pain control, mouth opening and patient preferences. This is supported by other studies which proved efficacy of morphine gargles [36, 37, 39–44].

### **3.3 Morphine and vaginal mucositis**

Vaginitis, also known as vaginal mucositis is an acute inflammation with erythema and erosion of vaginal mucosa leading to severe vaginal pain, per vaginal discharge and/or associated complications. It is commonly seen in patients with local infection or as a part of systemic infection, as a complication to radiotherapy to local areas or chemotherapy, recto-vaginal fistula, trauma, etc. Morphine, similar to its role in oral mucositis can be considered for vaginal mucositis. A case reported by Ostwal et al. [45] showed efficacy of morphine when combined with vaginal douche (magic vaginal douche—metronidazole, normal saline, povidone iodine solution, lignocaine viscous with 20 mg crushed tab morphine) in relief from symptoms of vaginal mucositis. However RCTs are not available and are required to prove its clinical efficacy.

### **4. Role of morphine in chronic cough**

### **4.1 Introduction**

Cough is found to be prevalent in around 65% patients with lung cancer [46] and 70% patients with COPD [47, 48]. Persistent or chronic cough can have various physical complications like musculoskeletal pain over chest wall, rib fracture, bowel and bladder incontinence, disturbed sleep and feeling of exhaustion. Patients usually experience psychological impacts, social isolation and decreased quality of life [48].

Cough reflex is regulated by vagal afferent pathways, nucleus tractus solitarius (NTS) in brainstem, and cough center in cerebral cortex. Common underlying patho-physiological causes for cough includes: (i) infection; (ii) lung cancer or secondary metastases to lung/pleura/mediastinum/pericardium/blood vessels; (iii) COPD, ILD, bronchiectasis; (iv) aspiration; (v) asthma/bronchospasm; (vi) esophageal reflux; (vii) tracheo-esophageal fistula; (viii) radiotherapy or chemotherapy induced pulmonary fibrosis; (ix) ACE inhibitors; (x) pulmonary edema/ left ventricular failure, etc. Timely and proper assessment of cough with removal of underlying cause can decrease distress and improve patients' quality of life.

### **4.2 Morphine and cough**

Research work by Kamei [49] showed involvement of mu opioid receptors in production of cough. Very limited studies are available for use of morphine on chronic cough [47, 50–56]. Strongest evidence for effectiveness of morphine in chronic cough was shown in a double blind placebo controlled trial by Morice et al. [57]. Twenty seven patients with chronic persistent cough were assigned to 4 weeks of slow release morphine sulfate (5 mg twice daily escalated to 10 mg twice daily) matched correspondingly with placebo. A significant improvement of 3.2 points

**31**

**7. Conclusion**

*Other Uses of Morphine*

from 5 to 10 mg twice daily.

**5. Role of morphine in diarrhea**

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

over baseline, and 40% rapid reduction in cough frequency and severity was

observed in slow release morphine group (*p* < 0.01). Dose comparison over 3 month period between 5 and 10 mg did not showed any significant difference, helping to conclude study with daily dose recommendation of slow release morphine sulfate

Diarrhea has been defined as "passage of ≥3 loose or watery bowel movements per day or passage of ≥200 g of stool per day based on typical diet." Diarrhea can be acute (<14 days), persistent (>14 days but <30 days) or chronic (>30 days) based on its duration. Diarrhea poses a common and significant problem in patients with cancer. It may be due to either local infection, as a part of systemic inflammation/

infection, as a complication to radiotherapy or chemotherapy [58], etc.

Till date robust studies supporting this has not been available.

**6. Morphine and opioid substitution therapy (OST)**

the quality of life and health of injecting drug users (IDUs).

necessity of more robust and clinically controlled trials.

Mechanism for diarrhea can be attributed to increased intestinal motility [59, 60]. Hence drugs which act to decrease intestinal motility are found to be helpful in treatment. Morphine and other opiates (loperamide, diphenoxylate, codeine) act on intestinal mu-receptors and slow intestinal transit time, thus increasing net absorption [61, 62]. Though constipation is commonly seen as a side effect with morphine use, research considering use of this side effect to treat diarrhea has not been done. Clinical Practice guidelines by European Society for Medical Oncology (ESMO) has documented role of tincture of opium like morphine (10 mg/mL morphine) in treatment with diarrhea as an alternative to loperamide. The recommended dose of tincture morphine is 10–15 drops in water every 3–4 h [58, 63, 64].

Morphine has been known for its potential effect in analgesia since last few decades. However, it is also known for its potential to cause addiction and dependence. Opium, derived naturally from poppy plant is widely used for addiction. Opioid substitution therapy (OST) is an evidence-based intervention for opiate dependent persons that replaces illicit drug use with medically prescribed, orally administered opiates such as buprenorphine and methadone. OST reduces HIV risk behaviors and harms associated with injecting (such as abscesses, septicemia and endocarditis), overdose and participation in criminal activity, thereby improving

Work by Hämmig et al. [65] showed that slow release oral morphine (SROM) preparations can be used as OST for heroin addicted patients. Authors found higher treatment satisfaction, fewer cravings for drug and less mental stress with SROM. Cochrane review by Ferri et al. [65] found only three randomized controlled trials which included SROM for OST. Out of three, only two studies suggested possible role of SROM formulations; while remaining study was associated with adverse events like depressive symptoms [65–70]. Hence authors concluded for

Morphine, a potent and strong opioid, has shown its efficacy in relieving variety of distressing symptoms. Research has documented role of low dose morphine for

*Opioids - From Analgesic Use to Addiction*

efficacy of morphine gargles [36, 37, 39–44].

**4. Role of morphine in chronic cough**

**3.3 Morphine and vaginal mucositis**

prove its clinical efficacy.

**4.2 Morphine and cough**

**4.1 Introduction**

life [48].

Various combination of local measures helps to take care of mucositis-related complications. Research has shown effectiveness of morphine gargles either alone (morphine rinse) or in combination with antacid, lignocaine viscous and dextromethorphan (magic mouth wash), in relieving pain and symptoms related to mucositis. A mini review by Dutta et al. [38] compared six studies using morphine as oral rinse. All studies showed satisfactory result in terms of pain control, mouth opening and patient preferences. This is supported by other studies which proved

Vaginitis, also known as vaginal mucositis is an acute inflammation with erythema and erosion of vaginal mucosa leading to severe vaginal pain, per vaginal discharge and/or associated complications. It is commonly seen in patients with local infection or as a part of systemic infection, as a complication to radiotherapy to local areas or chemotherapy, recto-vaginal fistula, trauma, etc. Morphine, similar to its role in oral mucositis can be considered for vaginal mucositis. A case reported by Ostwal et al. [45] showed efficacy of morphine when combined with vaginal douche (magic vaginal douche—metronidazole, normal saline, povidone iodine solution, lignocaine viscous with 20 mg crushed tab morphine) in relief from symptoms of vaginal mucositis. However RCTs are not available and are required to

Cough is found to be prevalent in around 65% patients with lung cancer [46] and 70% patients with COPD [47, 48]. Persistent or chronic cough can have various physical complications like musculoskeletal pain over chest wall, rib fracture, bowel and bladder incontinence, disturbed sleep and feeling of exhaustion. Patients usually experience psychological impacts, social isolation and decreased quality of

Cough reflex is regulated by vagal afferent pathways, nucleus tractus solitarius (NTS) in brainstem, and cough center in cerebral cortex. Common underlying patho-physiological causes for cough includes: (i) infection; (ii) lung cancer or secondary metastases to lung/pleura/mediastinum/pericardium/blood vessels; (iii) COPD, ILD, bronchiectasis; (iv) aspiration; (v) asthma/bronchospasm; (vi) esophageal reflux; (vii) tracheo-esophageal fistula; (viii) radiotherapy or chemotherapy induced pulmonary fibrosis; (ix) ACE inhibitors; (x) pulmonary edema/ left ventricular failure, etc. Timely and proper assessment of cough with removal of

underlying cause can decrease distress and improve patients' quality of life.

Research work by Kamei [49] showed involvement of mu opioid receptors in production of cough. Very limited studies are available for use of morphine on chronic cough [47, 50–56]. Strongest evidence for effectiveness of morphine in chronic cough was shown in a double blind placebo controlled trial by Morice et al. [57]. Twenty seven patients with chronic persistent cough were assigned to 4 weeks of slow release morphine sulfate (5 mg twice daily escalated to 10 mg twice daily) matched correspondingly with placebo. A significant improvement of 3.2 points

**30**

over baseline, and 40% rapid reduction in cough frequency and severity was observed in slow release morphine group (*p* < 0.01). Dose comparison over 3 month period between 5 and 10 mg did not showed any significant difference, helping to conclude study with daily dose recommendation of slow release morphine sulfate from 5 to 10 mg twice daily.

### **5. Role of morphine in diarrhea**

Diarrhea has been defined as "passage of ≥3 loose or watery bowel movements per day or passage of ≥200 g of stool per day based on typical diet." Diarrhea can be acute (<14 days), persistent (>14 days but <30 days) or chronic (>30 days) based on its duration. Diarrhea poses a common and significant problem in patients with cancer. It may be due to either local infection, as a part of systemic inflammation/ infection, as a complication to radiotherapy or chemotherapy [58], etc.

Mechanism for diarrhea can be attributed to increased intestinal motility [59, 60]. Hence drugs which act to decrease intestinal motility are found to be helpful in treatment. Morphine and other opiates (loperamide, diphenoxylate, codeine) act on intestinal mu-receptors and slow intestinal transit time, thus increasing net absorption [61, 62]. Though constipation is commonly seen as a side effect with morphine use, research considering use of this side effect to treat diarrhea has not been done. Clinical Practice guidelines by European Society for Medical Oncology (ESMO) has documented role of tincture of opium like morphine (10 mg/mL morphine) in treatment with diarrhea as an alternative to loperamide. The recommended dose of tincture morphine is 10–15 drops in water every 3–4 h [58, 63, 64]. Till date robust studies supporting this has not been available.

### **6. Morphine and opioid substitution therapy (OST)**

Morphine has been known for its potential effect in analgesia since last few decades. However, it is also known for its potential to cause addiction and dependence. Opium, derived naturally from poppy plant is widely used for addiction. Opioid substitution therapy (OST) is an evidence-based intervention for opiate dependent persons that replaces illicit drug use with medically prescribed, orally administered opiates such as buprenorphine and methadone. OST reduces HIV risk behaviors and harms associated with injecting (such as abscesses, septicemia and endocarditis), overdose and participation in criminal activity, thereby improving the quality of life and health of injecting drug users (IDUs).

Work by Hämmig et al. [65] showed that slow release oral morphine (SROM) preparations can be used as OST for heroin addicted patients. Authors found higher treatment satisfaction, fewer cravings for drug and less mental stress with SROM. Cochrane review by Ferri et al. [65] found only three randomized controlled trials which included SROM for OST. Out of three, only two studies suggested possible role of SROM formulations; while remaining study was associated with adverse events like depressive symptoms [65–70]. Hence authors concluded for necessity of more robust and clinically controlled trials.

### **7. Conclusion**

Morphine, a potent and strong opioid, has shown its efficacy in relieving variety of distressing symptoms. Research has documented role of low dose morphine for

treatment and relief from conditions like chronic, refractory breathlessness, cough, mucositis (oral/vaginal). However, more robust studies are required to establish its clinical efficacy in diarrhea and opioid substitution therapy.

### **Conflicts of interest**

None.

### **Author details**

Shrenik Ostwal Narayana Super Speciality Hospital, Howrah, West Bengal, India

\*Address all correspondence to: drshrenikostwal@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**33**

*Other Uses of Morphine*

2012;**185**(4):435-452

2001;**21**(4):323-329

2006;**31**(1):58-69

1986;**89**(2):234-236

1989;**82**(5):264-267

2015;**147**(1):232-241

2011;**106**(4):463-474

2009;**33**(4):771-777

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

[10] Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: A systematic review. Journal of Clinical Oncology. 2008;**26**(14):2396-2404

[11] Cabezón-Gutiérrez L, Khosravi-Shahi P, Custodio-Cabello S, Muñiz-González F, Cano-Aguirre M d P, Alonso-Viteri S. Opioids for management of episodic breathlessness or dyspnea in patients with advanced disease. Supportive Care in Cancer.

[12] Currow D et al. A pragmatic, phase III, multisite, double-blind, placebocontrolled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, exertion and morphine sulfate (BEAMS) study protocol On behalf of the Australian National Palliative Care Clinical Studies Collaborative (PaCCSC). BMJ Open.

[13] Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database of Systematic Reviews. 31 Mar 2016;**3**:CD011008. DOI: 10.1002/14651858.CD011008.pub2

[14] Afolabi TM, Nahata MC, Pai V. Nebulized opioids for the palliation of dyspnea in terminally ill patients. American Journal of Health-System Pharmacy. 2017;**74**(14):1053-1061

[15] Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnea of terminal cancer patients. Journal of Pain and Symptom Management. 1990;**5**(6):341-344

[16] Kloke M, Cherny N. Treatment of dyspnoea in advanced cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2015;**26**(5):69-73

2016;**24**(9):4045-4055

2017;**7**:18-100

Respiratory and Critical Care Medicine.

[2] Muers MF, Round CE. Palliation of symptoms in non-small cell lung cancer: A study by the Yorkshire Regional Cancer Organisation thoracic group.

[3] Smith EL et al. Dyspnea, anxiety, body consciousness, and quality of life in patients with lung cancer. Journal of Pain and Symptom Management.

[4] Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. Journal of Pain and Symptom Management.

[5] Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest.

[6] Higginson I, McCarthy M. Measuring symptoms in terminal cancer: Are pain and dyspnoea controlled? Journal of the Royal Society of Medicine.

[7] Mahler DA, O'Donnell DE. Recent

[8] Nishino T. Dyspnoea: Underlying

[9] Mahler DA et al. Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. The European Respiratory Journal.

advances in dyspnea. Chest.

mechanisms and treatment. British Journal of Anaesthesia.

[1] Parshall MB et al. An official American thoracic society statement:

Update on the mechanisms, assessment, and management of dyspnoea. American Journal of

Thorax. 1993;**48**(4):339-343

### **References**

*Opioids - From Analgesic Use to Addiction*

**Conflicts of interest**

None.

treatment and relief from conditions like chronic, refractory breathlessness, cough, mucositis (oral/vaginal). However, more robust studies are required to establish its

clinical efficacy in diarrhea and opioid substitution therapy.

**32**

**Author details**

Shrenik Ostwal

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Narayana Super Speciality Hospital, Howrah, West Bengal, India

\*Address all correspondence to: drshrenikostwal@gmail.com

[1] Parshall MB et al. An official American thoracic society statement: Update on the mechanisms, assessment, and management of dyspnoea. American Journal of Respiratory and Critical Care Medicine. 2012;**185**(4):435-452

[2] Muers MF, Round CE. Palliation of symptoms in non-small cell lung cancer: A study by the Yorkshire Regional Cancer Organisation thoracic group. Thorax. 1993;**48**(4):339-343

[3] Smith EL et al. Dyspnea, anxiety, body consciousness, and quality of life in patients with lung cancer. Journal of Pain and Symptom Management. 2001;**21**(4):323-329

[4] Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. Journal of Pain and Symptom Management. 2006;**31**(1):58-69

[5] Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest. 1986;**89**(2):234-236

[6] Higginson I, McCarthy M. Measuring symptoms in terminal cancer: Are pain and dyspnoea controlled? Journal of the Royal Society of Medicine. 1989;**82**(5):264-267

[7] Mahler DA, O'Donnell DE. Recent advances in dyspnea. Chest. 2015;**147**(1):232-241

[8] Nishino T. Dyspnoea: Underlying mechanisms and treatment. British Journal of Anaesthesia. 2011;**106**(4):463-474

[9] Mahler DA et al. Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. The European Respiratory Journal. 2009;**33**(4):771-777

[10] Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: A systematic review. Journal of Clinical Oncology. 2008;**26**(14):2396-2404

[11] Cabezón-Gutiérrez L, Khosravi-Shahi P, Custodio-Cabello S, Muñiz-González F, Cano-Aguirre M d P, Alonso-Viteri S. Opioids for management of episodic breathlessness or dyspnea in patients with advanced disease. Supportive Care in Cancer. 2016;**24**(9):4045-4055

[12] Currow D et al. A pragmatic, phase III, multisite, double-blind, placebocontrolled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, exertion and morphine sulfate (BEAMS) study protocol On behalf of the Australian National Palliative Care Clinical Studies Collaborative (PaCCSC). BMJ Open. 2017;**7**:18-100

[13] Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database of Systematic Reviews. 31 Mar 2016;**3**:CD011008. DOI: 10.1002/14651858.CD011008.pub2

[14] Afolabi TM, Nahata MC, Pai V. Nebulized opioids for the palliation of dyspnea in terminally ill patients. American Journal of Health-System Pharmacy. 2017;**74**(14):1053-1061

[15] Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnea of terminal cancer patients. Journal of Pain and Symptom Management. 1990;**5**(6):341-344

[16] Kloke M, Cherny N. Treatment of dyspnoea in advanced cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2015;**26**(5):69-73

[17] Thomas JR, von Gunten CF. Clinical management of dyspnoea. The Lancet Oncology. 2002;**3**(4):223-228

[18] Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: A systematic review and meta-analysis. Acta Oncologica. 2012;**51**(8):996-1008

[19] Mahler DA. Opioids for refractory dyspnea. Expert Review of Respiratory Medicine. 2013;**7**(2):123-135

[20] Tian C, Wang JY, Wang ML, Jiang B, Zhang LL, Liu F. Morphine versus methylprednisolone or aminophylline for relieving dyspnea in patients with advanced cancer in China: A retrospective study. Springerplus. 2016;**5**(1):1945

[21] Jennings A-L, Davies AN, Higgins JPT, Gibbs JSR, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;**57**(11):939-944

[22] Clemens KE, Quednau I, Klaschik E. Is there a higher risk of respiratory depression in opioid-naïve palliative care patients during symptomatic therapy of dyspnea with strong opioids? Journal of Palliative Medicine. 2008;**11**(2):204-216

[23] Charles MA, Reymond L, Israel F. Relief of incident dyspnea in palliative cancer patients: A pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. Journal of Pain and Symptom Management. 2008;**36**(1):29-38

[24] Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: A randomized double-blind controlled trial. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO. 1999;**10**(12):1511-1514

[25] Grimbert D et al. Dyspnea and morphine aerosols in the palliative care of lung cancer. Revue des Maladies Respiratoires. 2004;**21**(6):1091-1097

[26] Schwartzman RJ, Patel M, Grothusen JR, Alexander GM. Efficacy of 5-day continuous lidocaine infusion for the treatment of refractory complex regional pain syndrome. Pain Medicine. 2009;**10**(2):401-412

[27] Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ [British Medical Journal]. 2003;**327**(7414):523-528

[28] Johnson MJ, Mcdonagh TA, Harkness A, Mckay SE, Dargie HJ, Infirmary GR. Morphine for the relief of breathlessness in patients with chronic heart failure—A pilot study. The European Journal of Heart Failure. 2002;**4**:753-756

[29] Oxberry SG, Bland JM, Clark AL, Cleland JG, Johnson MJ. Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough. Journal of Palliative Medicine. 2013;**16**(3):250-255

[30] Shohrati M, Ghanei M, Harandi AA, Foroghi S, Harandi AA. Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: A double-blind randomized clinical trial study. Pulmonary medicine. 2012;**2012**:1-6

[31] Matsuda Y et al. Low-dose morphine for dyspnea in terminally ill patients with idiopathic interstitial pneumonias. Journal of Palliative Medicine. 2017;**20**(8):879-883

[32] Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marciniuk DD. Low-dose nebulized morphine

**35**

*Other Uses of Morphine*

1995;**152**(6):1940-1945

2002;**3**:CD002872

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

does not improve exercise in interstitial lung disease. American Journal of Respiratory and Critical Care Medicine. [41] Saunders DP et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients. Supportive Care in Cancer. 2013;**21**(11):3191-3207

[42] Quinn B. Efficacy of a

supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: A review of current data. European Journal of Cancer Care. 2013;**22**(5):564-579

[43] Cerchietti LCA et al. Effect of topical morphine for mucositisassociated pain following concomitant

[44] Chan A, Ignoffo RJ. Survey of topical oral solutions for the treatment of chemo-induced oral mucositis. Journal of Oncology Pharmacy Practice.

[45] Anandi Q, Ostwal S, Patel H, Sanghavi P. Magic vaginal douche for severe vaginal mucositis: A case-based approach. International Journal of Palliative Nursing. 2018;**1**(1):17-18

[46] Kvale PA. Chronic cough due to lung tumors ACCP evidence-based clinical practice guidelines. Chest. Jan 2006;**129**(1 Suppl):147S-153S. DOI: 10.1378/chest.129.1\_suppl.147S

[47] Molassiotis A et al. Clinical expert guidelines for the management of cough in lung cancer: Report of a UK task group on cough. Cough. 2010;**6**(1):9

[48] Molassiotis A, Bailey C, Caress A, Tan JY. Interventions for cough in cancer. Cochrane Database of Systematic Reviews. 2010;**9**:

[49] Kamei J. Role of opioidergic and serotonergic mechanisms in cough and

CD007881

chemoradiotherapy for head and neck carcinoma. Cancer. 2002;**95**(10):2230-2236

2005;**11**(4):139-143

[33] Polosa R, Simidchiev A, Walters EH. Nebulised morphine for severe interstitial lung disease. Cochrane Database of Systematic Reviews.

[34] Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy: Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;**98**(7):1531-1539

[35] Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dental Clinics of North America. 2008;**52**(1):61-77

[36] Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO Clinical Practice Guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;**120**(10):1453-1461

[37] Joanna Briggs Institute. Prevention and treatment of oral mucositis in cancer patients. Best Practice.

[38] Dutta K, Garg R, Garg R. Palliative medicine and hospice care morphine mouthwash in oral mucositis: A mini review. The American Journal of Hospice & Palliative Care. 2016;**2**(2):26-29

[39] Saroja G, Devi PS, Namrata R. Oral morphine solution as an oral rinse or mouth gargle for mucositis pain. Indian Journal of Palliative Care.

[40] Sarvizadeh M, Hemati S, Meidani M, Ashouri M, Roayaei M, Shahsanai A. Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer. Advanced Biomedical Research.

1998;**2**(3):1-6

2010;**16**(1):54-55

2015;**4**(1):44

*Other Uses of Morphine DOI: http://dx.doi.org/10.5772/intechopen.85165*

*Opioids - From Analgesic Use to Addiction*

Oncology. 2002;**3**(4):223-228

Medicine. 2013;**7**(2):123-135

[18] Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: A systematic review and meta-analysis. Acta Oncologica. 2012;**51**(8):996-1008

[19] Mahler DA. Opioids for refractory dyspnea. Expert Review of Respiratory

[20] Tian C, Wang JY, Wang ML, Jiang B, Zhang LL, Liu F. Morphine versus methylprednisolone or aminophylline for relieving dyspnea in patients with advanced cancer in China: A retrospective study. Springerplus. 2016;**5**(1):1945

[21] Jennings A-L, Davies AN, Higgins JPT, Gibbs JSR, Broadley KE. A

systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;**57**(11):939-944

[22] Clemens KE, Quednau I, Klaschik E. Is there a higher risk of respiratory depression in opioid-naïve palliative care patients during symptomatic therapy of dyspnea with strong

opioids? Journal of Palliative Medicine.

[23] Charles MA, Reymond L, Israel F. Relief of incident dyspnea in palliative cancer patients: A pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. Journal of Pain and Symptom Management. 2008;**36**(1):29-38

[24] Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: A randomized double-blind controlled trial. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO.

1999;**10**(12):1511-1514

2008;**11**(2):204-216

[17] Thomas JR, von Gunten CF. Clinical management of dyspnoea. The Lancet

[25] Grimbert D et al. Dyspnea and morphine aerosols in the palliative care of lung cancer. Revue des Maladies Respiratoires. 2004;**21**(6):1091-1097

[26] Schwartzman RJ, Patel M,

[27] Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ [British Medical Journal]. 2003;**327**(7414):523-528

[28] Johnson MJ, Mcdonagh TA, Harkness A, Mckay SE, Dargie HJ, Infirmary GR. Morphine for the relief of breathlessness in patients with chronic heart failure—A pilot study. The European Journal of Heart Failure.

[29] Oxberry SG, Bland JM, Clark AL, Cleland JG, Johnson MJ. Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough. Journal of Palliative Medicine. 2013;**16**(3):250-255

[30] Shohrati M, Ghanei M, Harandi AA, Foroghi S, Harandi AA. Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: A double-blind randomized clinical trial study. Pulmonary medicine.

[31] Matsuda Y et al. Low-dose morphine for dyspnea in terminally ill patients with idiopathic interstitial pneumonias.

[32] Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marciniuk DD. Low-dose nebulized morphine

Journal of Palliative Medicine.

2002;**4**:753-756

2012;**2012**:1-6

2017;**20**(8):879-883

2009;**10**(2):401-412

Grothusen JR, Alexander GM. Efficacy of 5-day continuous lidocaine infusion for the treatment of refractory complex regional pain syndrome. Pain Medicine.

**34**

does not improve exercise in interstitial lung disease. American Journal of Respiratory and Critical Care Medicine. 1995;**152**(6):1940-1945

[33] Polosa R, Simidchiev A, Walters EH. Nebulised morphine for severe interstitial lung disease. Cochrane Database of Systematic Reviews. 2002;**3**:CD002872

[34] Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy: Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;**98**(7):1531-1539

[35] Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dental Clinics of North America. 2008;**52**(1):61-77

[36] Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO Clinical Practice Guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;**120**(10):1453-1461

[37] Joanna Briggs Institute. Prevention and treatment of oral mucositis in cancer patients. Best Practice. 1998;**2**(3):1-6

[38] Dutta K, Garg R, Garg R. Palliative medicine and hospice care morphine mouthwash in oral mucositis: A mini review. The American Journal of Hospice & Palliative Care. 2016;**2**(2):26-29

[39] Saroja G, Devi PS, Namrata R. Oral morphine solution as an oral rinse or mouth gargle for mucositis pain. Indian Journal of Palliative Care. 2010;**16**(1):54-55

[40] Sarvizadeh M, Hemati S, Meidani M, Ashouri M, Roayaei M, Shahsanai A. Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer. Advanced Biomedical Research. 2015;**4**(1):44

[41] Saunders DP et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients. Supportive Care in Cancer. 2013;**21**(11):3191-3207

[42] Quinn B. Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: A review of current data. European Journal of Cancer Care. 2013;**22**(5):564-579

[43] Cerchietti LCA et al. Effect of topical morphine for mucositisassociated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer. 2002;**95**(10):2230-2236

[44] Chan A, Ignoffo RJ. Survey of topical oral solutions for the treatment of chemo-induced oral mucositis. Journal of Oncology Pharmacy Practice. 2005;**11**(4):139-143

[45] Anandi Q, Ostwal S, Patel H, Sanghavi P. Magic vaginal douche for severe vaginal mucositis: A case-based approach. International Journal of Palliative Nursing. 2018;**1**(1):17-18

[46] Kvale PA. Chronic cough due to lung tumors ACCP evidence-based clinical practice guidelines. Chest. Jan 2006;**129**(1 Suppl):147S-153S. DOI: 10.1378/chest.129.1\_suppl.147S

[47] Molassiotis A et al. Clinical expert guidelines for the management of cough in lung cancer: Report of a UK task group on cough. Cough. 2010;**6**(1):9

[48] Molassiotis A, Bailey C, Caress A, Tan JY. Interventions for cough in cancer. Cochrane Database of Systematic Reviews. 2010;**9**: CD007881

[49] Kamei J. Role of opioidergic and serotonergic mechanisms in cough and antitussives. Pulmonary Pharmacology. 1996;**9**(5-6):349-356

[50] Dudgeon DJ. Managing dyspnea and cough. Hematology/ Oncology Clinics of North America. 2002;**16**(3):557-577

[51] An HJ, Kim I-K, Lee JE, Kang Y-J, Kim CH, Kim H-K. Nebulized morphine for intractable cough in advanced cancer: Two case reports. Journal of Palliative Medicine. 2015;**18**(3):278-281

[52] Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS. Treatment of unexplained chronic cough chest guideline and expert panel report. Chest. 2016;**149**(1):27-44

[53] Wee B et al. Management of chronic cough in patients receiving palliative care: Review of evidence and recommendations by a task group of the Association for Palliative Medicine of Great Britain and Ireland. Palliative Medicine. 2012;**26**(6):780-787

[54] Stein WM, Min YK. Nebulized morphine for paroxysmal cough and dyspnea in a nursing home resident with metastatic cancer. American Journal of Hospice and Palliative Medicine. 1997;**14**(2):52-56

[55] Borja-Cacho D, Matthews J. NIH public access. Nano. 2008;**6**(9):2166-2171

[56] Badri H, Satia I, Woodcock A, Smith J. The use of low dose morphine for the management of chronic cough in a tertiary cough clinic background: Objective: Methods. American Journal of Respiratory and Critical Care Medicine. 2015;**191**:A4117

[57] Morice AH et al. Opiate therapy in chronic cough. American Journal of Respiratory and Critical Care Medicine. 2007;**175**(4):312-315

[58] Bush SH et al. Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2018;**29**(4):iv126-iv142

[59] Porreca F, Heyman JS, Mosberg HI, Omnaas JR, Vaught JL. Role of mu and delta receptors in the supraspinal and spinal analgesic effects of [D-Pen2, D-Pen5] enkephalin in the mouse. The Journal of Pharmacology and Experimental Therapeutics. 1987;**241**(2):393-400

[60] Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterology and Motility. 2004;**16**(s2):17-28

[61] Kaufman PN et al. Role of opiate receptors in the regulation of colonic transit. Gastroenterology. 1988;**94**:1351-1356

[62] Sternini C, Patierno S, Selmer I-S, Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterology and Motility. 2004;**16**(s2):3-16

[63] Cherny NI. Evaluation and management of treatment-related diarrhea in patients with advanced cancer: A review. Journal of Pain and Symptom Management. 2008;**36**(4):413-423

[64] Schiller LR, Pardi DS, Sellin JH. Chronic diarrhea: Diagnosis and management. Clinical Gastroenterology and Hepatology. 2017;**15**(2):182-193

[65] Hämmig R et al. Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. Journal of Substance Abuse Treatment. 2014;**47**(4):275-281

[66] Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid

**37**

*Other Uses of Morphine*

*DOI: http://dx.doi.org/10.5772/intechopen.85165*

dependence. Cochrane Database of Systematic Reviews. 2013;**6**:CD009879. DOI: 10.1002/14651858.CD009879.pub2

[67] Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N, Fischer G. Comparative study of the effectiveness of slow-release

2005;**100**(8):1101-1109

2006;**41**(2):223-244

2013;**109**:617-626

Research. 2005;**11**(3):145-151

[69] Giacomuzzi S, Kemmler G, Ertl M, Riemer Y. Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants. Substance Use & Misuse.

[70] Beck T et al. Maintenance treatment for opioid dependence with slow-release oral morphine: A randomized cross-over, non-inferiority study versus methadone. Addiction.

morphine and methadone for opioid maintenance therapy. Addiction.

[68] Kraigher D et al. Use of slow-release oral morphine for the treatment of opioid dependence. European Addiction *Other Uses of Morphine DOI: http://dx.doi.org/10.5772/intechopen.85165*

*Opioids - From Analgesic Use to Addiction*

1996;**9**(5-6):349-356

2002;**16**(3):557-577

2015;**18**(3):278-281

[50] Dudgeon DJ. Managing dyspnea and cough. Hematology/ Oncology Clinics of North America.

[51] An HJ, Kim I-K, Lee JE, Kang Y-J, Kim CH, Kim H-K. Nebulized morphine for intractable cough in advanced cancer: Two case reports. Journal of Palliative Medicine.

[52] Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS. Treatment of unexplained chronic cough chest guideline and expert panel report. Chest. 2016;**149**(1):27-44

[53] Wee B et al. Management of chronic cough in patients receiving palliative care: Review of evidence and recommendations by a task group of the Association for Palliative Medicine of Great Britain and Ireland. Palliative

Medicine. 2012;**26**(6):780-787

[55] Borja-Cacho D, Matthews J. NIH public access. Nano. 2008;**6**(9):2166-2171

[56] Badri H, Satia I, Woodcock A, Smith J. The use of low dose morphine for the management of chronic cough in a tertiary cough clinic background: Objective: Methods. American Journal of Respiratory and Critical Care Medicine. 2015;**191**:A4117

[57] Morice AH et al. Opiate therapy in chronic cough. American Journal of Respiratory and Critical Care Medicine.

2007;**175**(4):312-315

1997;**14**(2):52-56

[54] Stein WM, Min YK. Nebulized morphine for paroxysmal cough and dyspnea in a nursing home resident with metastatic cancer. American Journal of Hospice and Palliative Medicine.

antitussives. Pulmonary Pharmacology.

[58] Bush SH et al. Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology.

[59] Porreca F, Heyman JS, Mosberg HI, Omnaas JR, Vaught JL. Role of mu and delta receptors in the supraspinal

[60] Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterology and Motility.

and spinal analgesic effects of [D-Pen2, D-Pen5] enkephalin in the mouse. The Journal of Pharmacology and Experimental Therapeutics.

[61] Kaufman PN et al. Role of opiate receptors in the regulation of colonic transit. Gastroenterology.

[62] Sternini C, Patierno S, Selmer I-S, Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterology and Motility.

[63] Cherny NI. Evaluation and management of treatment-related diarrhea in patients with advanced cancer: A review. Journal of Pain and Symptom Management.

[64] Schiller LR, Pardi DS, Sellin JH.

Gastroenterology and Hepatology.

[66] Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid

[65] Hämmig R et al. Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. Journal of Substance Abuse Treatment.

Chronic diarrhea: Diagnosis and management. Clinical

2018;**29**(4):iv126-iv142

1987;**241**(2):393-400

2004;**16**(s2):17-28

1988;**94**:1351-1356

2004;**16**(s2):3-16

2008;**36**(4):413-423

2017;**15**(2):182-193

2014;**47**(4):275-281

**36**

dependence. Cochrane Database of Systematic Reviews. 2013;**6**:CD009879. DOI: 10.1002/14651858.CD009879.pub2

[67] Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N, Fischer G. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction. 2005;**100**(8):1101-1109

[68] Kraigher D et al. Use of slow-release oral morphine for the treatment of opioid dependence. European Addiction Research. 2005;**11**(3):145-151

[69] Giacomuzzi S, Kemmler G, Ertl M, Riemer Y. Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants. Substance Use & Misuse. 2006;**41**(2):223-244

[70] Beck T et al. Maintenance treatment for opioid dependence with slow-release oral morphine: A randomized cross-over, non-inferiority study versus methadone. Addiction. 2013;**109**:617-626

**39**

Section 3

Pathophysiology and

Therapeutic Strategies for

Opioid Addiction

### Section 3
