**2.2 Side effects**

*Pain Management - Practices, Novel Therapies and Bioactives*

**2.1 Mechanism of action**

intestine), cardiovascular events (myocardial infarction, hypertension exacerbation) and renal toxicity (acute renal failure, electrolyte and fluid abnormalities).

Prostaglandins are lipid compounds that are physiologically active and have a diverse range of homeostatic and inflammatory effects in the human body that modulate fever and pain. They are the primary mediators of inflammatory cascades resulting in peripheral sensitization, hyperalgesia and chronic pain. Prostaglandin H2 (PGH2) is a common precursor for prostaglandins (PGE2, PGI2, and PGF2) and thromboxane. It is synthesized from arachidonic acid via the rate limiting enzyme cyclooxygenase (COX) (**Figure 1**). By inhibiting the cyclooxygenase (COX) enzymes and thus inhibiting prostaglandin synthesis, NSAIDs are able to produce their analgesic and anti-inflammatory effects. COX exists in two isoforms, COX-1 and COX-2. COX-1 is expressed throughout the body and is a normal component of most cells. It is a necessary in the production of protective gastric mucosal secretions and regulation of gastric acid, promotion of platelet aggregation and the maintenance of renal blood flow [9]. COX-2, however, is minimally expressed and tightly regulated under normal conditions but is induced with the pro-inflammatory stimuli seen with cellular injury (IL-1, TNF-alpha tumor necrosis factor–alpha, and cytokines) [10]. Given some of the beneficial aspects of COX-1 and the specific pro-inflammatory aspect of COX-2, newer NSAIDs are directly targeted at selective

**258**

**Figure 1.**

*Production and actions of prostaglandins and thromboxane (adapted from [8]).*

The same mechanism of action that provides the therapeutic effect of NSAIDs is also most commonly responsible for the side effects associated with chronic use. By inhibiting prostaglandin synthesis, NSAIDs increase the risk of gastrointestinal bleeding [12–16], thrombosis [17], and myocardial infarction [18]. COX-1 mediated synthesis of PGE2 is responsible for gastric mucosa integrity. Inhibiting PGE2


*Adapted from [11].*

*\* Only generic names provided. List not all inclusive. Keep in mind NSAIDs carry varying risks of rare liver toxicity and renal failure.*

*• Selectivity is based on in vitro assay studies and should be interpreted with caution as different assay methods give different results. No assay method can predict what will happen when the drug is given to patients. Clinical studies are the best way to determine the effects of NSAIDs in patients.*

#### **Table 1.**

*Safety comparison of some of the most commonly used NSAIDs.\**

production with traditional non-selective NSAIDs results in gastric mucosal impairment and injury. Gastroduodenal ulcers are commonly identified with endoscopy after chronic non-selective NSAID use with double-blind trials showing incidence as high as 46% after 24 weeks of ibuprofen use [19]. Extra care must be taken with NSAID use in special populations including the elderly and those with underlying gastric irritation, stress related gastric mucosal injury (SRMD), and portal hypertensive gastropathy.

Given the side effects associated with inhibition of COX-1, especially the GI toxicity noted above, selective COX-2 inhibiting NSAIDs were created with the intention of avoiding harmful GI events while continuing to retain the antiinflammatory and analgesic benefits of COX-2 antagonism. The selective COX-2 inhibition that occurs with coxibs (celecoxib, rofecoxib) was, however, believed to be associated with increased cardiovascular (CV) events including hypertension and thrombosis. The CV side effects are attributed to the imbalance in vascular tone and clotting hemostasis that is in part regulated by arachidonic metabolites; with COX-1 mediated TXA2 being an inducer of platelet aggregation and COX-2 mediated PGI2 being an inhibitor of platelet aggregation [20]. This is highlighted with PGI2 receptor deficient mice being more prone to thrombosis then wild type mice [21]. Ultimately, large randomized controlled trials showed that celecoxib in moderate doses was non-inferior to naproxen or ibuprofen (non-selective NSAIDs) in regards to a primary outcome of cardiovascular causes of death [22].

## **3. Opioids**

Opioids have been used for the management of pain since the earliest records of human history. The Sumerians of Mesopotamia were the first to cultivate the poppy plant [23]. Further refinement paralleled the advancement of human growth with the first extraction of morphine from opium occurring in 1803 [24]. New formulations, concentrations, and routes of delivery were developed and there was a simultaneous increase in medicinal as well as recreational use. Opiate use peaked between 1999 and 2017 and was responsible for approximately 400,000 overdose related deaths [25]. This has culminated into the current state of affairs where narcotic prescription abuse has become a national crisis with strict regulations on prescribing now in place. The fine balance between proper medical uses for the treatment of acute and chronic pain versus inappropriate overprescribing is being heavily scrutinized requiring careful consideration of the appropriateness of initiating opioids and the risks and benefits of chronic use. The importance of this is demonstrated with meta-analysis showing roughly 5% of patients prescribed an opioid for pain developing iatrogenic opioid dependence or abuse [26]. One must have an intimate understanding of the various opioid medications available and take a careful and strategized approach to prescribing a chronic regimen to suitably navigate this dilemma. Nonetheless, opioids remain a mainstay in the treatment of acute and chronic cancer related pain. This is in contrast to the benefit of opioids used in chronic non-malignant pain with studies continuing to show little to no benefit in quality of life or functional capacity [27, 28].

#### **3.1 Mechanism of action**

The classification of *opioid* commonly refers to all compounds that bind to the opiate receptors. This includes the naturally occurring alkaloids derived from the opium poppy (morphine, codeine), semi-synthetic opioids which are synthesized

**261**

**Table 2.**

*NSAIDs, Opioids, and Beyond*

analgesic properties.

**3.2 Opioid receptors**

**Endogenous peptides**

Fentanyl Agonist

Methadone Agonist

**Agonists**

**Antagonists**

*Adapted from [29, 30].*

*Analgesic effects at opioid receptors.*

*DOI: http://dx.doi.org/10.5772/intechopen.93843*

from naturally occurring opiates (oxycodone, heroin) and fully synthetic opioids (methadone, fentanyl). Opioids as a class are similar in that they all cause analgesia and have a common side effect profile. Opioid drugs impart their effects primarily through three receptors: Mu (μ), Delta (δ), and Kappa (κ) (**Table 2**). These receptors are found both peripherally and centrally and can be activated all along the neuroaxis including the cortex, brainstem, interneurons of the spinal cord and the nociceptors at the level of the primary sensory neurons. Activation of these receptors is responsible for both the analgesic properties of opioids as well as the major side effects. All opioid receptors are G-protein coupled receptors that inhibit adenylyl cyclase, decreasing conductance of voltage-gated Ca++ channels and/or opening rectifying K+ channels (**Figure 2**). This ultimately prevents calcium influx and the release of pronociceptive neurotransmitters (glutamate, substance P, and calcitonin gene-related peptide from the nociceptive fibers) [31]. By preventing the release of these pain-promoting neurotransmitters, opioids are able to impart their

Mu receptors are largely thought of as the primary receptor responsible for analgesia with opioids; thus, the term "mu agonist" is often used to describe opioids used for the management of pain. Mu opioid receptors (MOR) are found in high density at the periaqueductal gray (PAG) of the midbrain. Agonism of MOR in this region is thought to eliminate a tonic gamma aminobutyric acid (GABA) tone thus

**Mu (**μ**) Delta (**δ**) Kappa (**κ**)**

Analgesia, spinal analgesia

antagonist

antagonist

Analgesia, sedation, dyspnea, psychomimetic effects, miosis, respiratory depression, euphoria,

dysphoria, dyspnea

Antagonist

Antagonist

Mu 1: Analgesia Mu 2: Sedation, vomiting, respiratory depression, pruritus, euphoria, anorexia, urinary retention, physical dependence

Enkephalins Agonist Agonist Beta-endorphin Agonist Agonist

Codeine Weak agonist Weak agonist

Meperidine Agonist Agonist

Naloxone Antagonist Weak

Naltrexone Antagonist Weak

Dynorphin A Agonist Agonist

Morphine Agonist Weak agonist

#### *NSAIDs, Opioids, and Beyond DOI: http://dx.doi.org/10.5772/intechopen.93843*

*Pain Management - Practices, Novel Therapies and Bioactives*

tensive gastropathy.

**3. Opioids**

production with traditional non-selective NSAIDs results in gastric mucosal impairment and injury. Gastroduodenal ulcers are commonly identified with endoscopy after chronic non-selective NSAID use with double-blind trials showing incidence as high as 46% after 24 weeks of ibuprofen use [19]. Extra care must be taken with NSAID use in special populations including the elderly and those with underlying gastric irritation, stress related gastric mucosal injury (SRMD), and portal hyper-

Given the side effects associated with inhibition of COX-1, especially the GI toxicity noted above, selective COX-2 inhibiting NSAIDs were created with the intention of avoiding harmful GI events while continuing to retain the antiinflammatory and analgesic benefits of COX-2 antagonism. The selective COX-2 inhibition that occurs with coxibs (celecoxib, rofecoxib) was, however, believed to be associated with increased cardiovascular (CV) events including hypertension and thrombosis. The CV side effects are attributed to the imbalance in vascular tone and clotting hemostasis that is in part regulated by arachidonic metabolites; with COX-1 mediated TXA2 being an inducer of platelet aggregation and COX-2 mediated PGI2 being an inhibitor of platelet aggregation [20]. This is highlighted with PGI2 receptor deficient mice being more prone to thrombosis then wild type mice [21]. Ultimately, large randomized controlled trials showed that celecoxib in moderate doses was non-inferior to naproxen or ibuprofen (non-selective NSAIDs)

in regards to a primary outcome of cardiovascular causes of death [22].

Opioids have been used for the management of pain since the earliest records of human history. The Sumerians of Mesopotamia were the first to cultivate the poppy plant [23]. Further refinement paralleled the advancement of human growth with the first extraction of morphine from opium occurring in 1803 [24]. New formulations, concentrations, and routes of delivery were developed and there was a simultaneous increase in medicinal as well as recreational use. Opiate use peaked between 1999 and 2017 and was responsible for approximately 400,000 overdose related deaths [25]. This has culminated into the current state of affairs where narcotic prescription abuse has become a national crisis with strict regulations on prescribing now in place. The fine balance between proper medical uses for the treatment of acute and chronic pain versus inappropriate overprescribing is being heavily scrutinized requiring careful consideration of the appropriateness of initiating opioids and the risks and benefits of chronic use. The importance of this is demonstrated with meta-analysis showing roughly 5% of patients prescribed an opioid for pain developing iatrogenic opioid dependence or abuse [26]. One must have an intimate understanding of the various opioid medications available and take a careful and strategized approach to prescribing a chronic regimen to suitably navigate this dilemma. Nonetheless, opioids remain a mainstay in the treatment of acute and chronic cancer related pain. This is in contrast to the benefit of opioids used in chronic non-malignant pain with studies continuing to show little to no benefit in quality of life or

The classification of *opioid* commonly refers to all compounds that bind to the opiate receptors. This includes the naturally occurring alkaloids derived from the opium poppy (morphine, codeine), semi-synthetic opioids which are synthesized

**260**

functional capacity [27, 28].

**3.1 Mechanism of action**

from naturally occurring opiates (oxycodone, heroin) and fully synthetic opioids (methadone, fentanyl). Opioids as a class are similar in that they all cause analgesia and have a common side effect profile. Opioid drugs impart their effects primarily through three receptors: Mu (μ), Delta (δ), and Kappa (κ) (**Table 2**). These receptors are found both peripherally and centrally and can be activated all along the neuroaxis including the cortex, brainstem, interneurons of the spinal cord and the nociceptors at the level of the primary sensory neurons. Activation of these receptors is responsible for both the analgesic properties of opioids as well as the major side effects. All opioid receptors are G-protein coupled receptors that inhibit adenylyl cyclase, decreasing conductance of voltage-gated Ca++ channels and/or opening rectifying K+ channels (**Figure 2**). This ultimately prevents calcium influx and the release of pronociceptive neurotransmitters (glutamate, substance P, and calcitonin gene-related peptide from the nociceptive fibers) [31]. By preventing the release of these pain-promoting neurotransmitters, opioids are able to impart their analgesic properties.
