**Table 2.**

*Analgesic effects at opioid receptors.*

**Figure 2.** *Mechanisms of opioid action in the spinal cord.*

indirectly stimulating descending inhibitory pathways at the level of the spinal cord [32]. MOR receptors are also in high density on dorsal horn neurons and elicit their analgesic effect through inhibition of glutamine release decreasing the transmission of nociceptive information from A-delta and C nerve fibers.

The drugs that are able to fully activate these mu receptors in a dose dependent fashion are referred to as full agonists. This is in contrast to the drugs that are either weak agonists at the mu receptor (while preventing other full agonists from binding) or are antagonists at the mu receptor while being an agonist at another receptor. These are referred to as agonist-antagonist drugs and include buprenorphine+naloxone (suboxone), nalbuphine, and pentazocine. Reversal of the effects caused by mu agonists is accomplished with competing antagonists (naloxone), which are crucial in the medical management of opioid overdoses and the associated respiratory depression. Kappa and delta receptors also contribute to analgesia and the other clinical effects seen with acute and chronic use including respiratory depression and sedation. Kappa receptors, in particular, are localized in the brain stem and spinal cord and are chiefly responsible for providing spinal analgesia [29]. Opioid receptors also bind to endogenous opioid

**263**

*NSAIDs, Opioids, and Beyond*

overall pain modulation.

of tolerance during abstinence.

**4. Antidepressants**

**3.3 Side effects**

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

peptides (endorphins, enkephalins, and dynorphins), which are important in

The clinical use of opioids is dependent upon more than just the receptor specificity and relies on deep understanding of the pharmacokinetics of these drugs for optimal use. In a basic sense, opioids can be classified into either short or long acting agents although this terminology inappropriately simplifies complex phar-

The interaction between exogenous opioids and opioid receptor activation has a diverse side effect profile with variable differences seen with acute and chronic use. These side effects include constipation, nausea and vomiting, hyperalgesia, opioid induced hormonal changes, and respiratory depression. Opioid induced constipation (OIC) is one of the most commonly seen side effects with roughly one half of patients experiencing OIC with long-term use [33]. OIC can cause significant morbidity with associated adverse effects including fecal impaction with obstruction, reflux, dyspepsia, cramping/pain, and lengthened hospitalization [34]. For this reason, all chronic opioid regimens should include prophylactic laxatives. Mu opioid receptors are abundant in the respiratory rhythm generating regions of the brainstem and pons. Agonism of these receptors causes opioid induced breathing alterations including significant reduction in respiratory rate and minute ventilation with associated hypercapnia. This can ultimately lead to fatal apnea, especially with lipophilic opioids and intravenous administration that allows for quick equilibration at the effect compartment (central respiratory centers) [35]. Given the euphoria that occurs with opioids, addiction is another potential iatrogenic side effect seen with acute and chronic use. This can be associated with tolerance to opioids, which is defined as a decreased objective and subjective effect with a stable dose over time as well as requiring increasing amount of an opioid to achieve the same effect. Increasing tolerance also develops to the other effects of opioids including respiratory depression [24]. This is problematic in patients abusing opioids given the tendency for relapse back to a previous dose that will now cause profound respiratory depression due to the loss

Antidepressants have a long established efficacy in the treatment of neuropathic predominant chronic pain disorders [36]. Neuropathic pain disorders develop from a multitude of disease processes that directly arise from lesions or other damage to the central or peripheral somatosensory nervous system [37]. Associated diseases and processes include diabetes mellitus (diabetic peripheral neuropathy), HIV (HIV polyneuropathy), herpes zoster (post-herpetic neuralgia), and medical interventions (e.g., post-mastectomy pain, chemotherapy). Tricyclic antidepressants (TCAs) including amitriptyline, imipramine, and nortriptyline are routinely used as first line options in the management of neuropathic pain [36, 38]. TCAs can be started and maintained at doses lower than the doses used in depression thus reducing some of the side effects commonly seen at depression doses such as dry mouth, sedation, urinary retention and orthostatic hypotension. TCAs must be used cautiously in patients taking other serotonergic drugs or in patients with a history of cardiovascular disorders, glaucoma, or urinary

macodynamic and pharmacokinetic properties of these drugs.

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

peptides (endorphins, enkephalins, and dynorphins), which are important in overall pain modulation.

The clinical use of opioids is dependent upon more than just the receptor specificity and relies on deep understanding of the pharmacokinetics of these drugs for optimal use. In a basic sense, opioids can be classified into either short or long acting agents although this terminology inappropriately simplifies complex pharmacodynamic and pharmacokinetic properties of these drugs.

#### **3.3 Side effects**

*Pain Management - Practices, Novel Therapies and Bioactives*

indirectly stimulating descending inhibitory pathways at the level of the spinal cord [32]. MOR receptors are also in high density on dorsal horn neurons and elicit their analgesic effect through inhibition of glutamine release decreasing the transmission

The drugs that are able to fully activate these mu receptors in a dose dependent fashion are referred to as full agonists. This is in contrast to the drugs that are either weak agonists at the mu receptor (while preventing other full agonists from binding) or are antagonists at the mu receptor while being an agonist at another receptor. These are referred to as agonist-antagonist drugs and include buprenorphine+naloxone (suboxone), nalbuphine, and pentazocine. Reversal of the effects caused by mu agonists is accomplished with competing antagonists (naloxone), which are crucial in the medical management of opioid overdoses and the associated respiratory depression. Kappa and delta receptors also contribute to analgesia and the other clinical effects seen with acute and chronic use including respiratory depression and sedation. Kappa receptors, in particular, are localized in the brain stem and spinal cord and are chiefly responsible for providing spinal analgesia [29]. Opioid receptors also bind to endogenous opioid

of nociceptive information from A-delta and C nerve fibers.

**262**

**Figure 2.**

*Mechanisms of opioid action in the spinal cord.*

The interaction between exogenous opioids and opioid receptor activation has a diverse side effect profile with variable differences seen with acute and chronic use. These side effects include constipation, nausea and vomiting, hyperalgesia, opioid induced hormonal changes, and respiratory depression. Opioid induced constipation (OIC) is one of the most commonly seen side effects with roughly one half of patients experiencing OIC with long-term use [33]. OIC can cause significant morbidity with associated adverse effects including fecal impaction with obstruction, reflux, dyspepsia, cramping/pain, and lengthened hospitalization [34]. For this reason, all chronic opioid regimens should include prophylactic laxatives. Mu opioid receptors are abundant in the respiratory rhythm generating regions of the brainstem and pons. Agonism of these receptors causes opioid induced breathing alterations including significant reduction in respiratory rate and minute ventilation with associated hypercapnia. This can ultimately lead to fatal apnea, especially with lipophilic opioids and intravenous administration that allows for quick equilibration at the effect compartment (central respiratory centers) [35]. Given the euphoria that occurs with opioids, addiction is another potential iatrogenic side effect seen with acute and chronic use. This can be associated with tolerance to opioids, which is defined as a decreased objective and subjective effect with a stable dose over time as well as requiring increasing amount of an opioid to achieve the same effect. Increasing tolerance also develops to the other effects of opioids including respiratory depression [24]. This is problematic in patients abusing opioids given the tendency for relapse back to a previous dose that will now cause profound respiratory depression due to the loss of tolerance during abstinence.

#### **4. Antidepressants**

Antidepressants have a long established efficacy in the treatment of neuropathic predominant chronic pain disorders [36]. Neuropathic pain disorders develop from a multitude of disease processes that directly arise from lesions or other damage to the central or peripheral somatosensory nervous system [37]. Associated diseases and processes include diabetes mellitus (diabetic peripheral neuropathy), HIV (HIV polyneuropathy), herpes zoster (post-herpetic neuralgia), and medical interventions (e.g., post-mastectomy pain, chemotherapy). Tricyclic antidepressants (TCAs) including amitriptyline, imipramine, and nortriptyline are routinely used as first line options in the management of neuropathic pain [36, 38]. TCAs can be started and maintained at doses lower than the doses used in depression thus reducing some of the side effects commonly seen at depression doses such as dry mouth, sedation, urinary retention and orthostatic hypotension. TCAs must be used cautiously in patients taking other serotonergic drugs or in patients with a history of cardiovascular disorders, glaucoma, or urinary

retention given the anticholinergic side effects TCAs can produce. Of note, TCAs are beneficial to both depressed and non-depressed patients as well as having the added value of helping with depression in the depressed subpopulation [36]. Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also commonly used in the management of chronic pain with duloxetine having FDA approval for the management of fibromyalgia and venlafaxine showing superiority to placebo in the treatment of diabetic neuropathy [39, 40].

The primary mechanism of action of TCAs in the treatment of neuropathic pain involves the reuptake inhibition of norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), which causes a blockade of the neuronal membrane ion channels and increases the activation of descending inhibitory pathways in the midbrain and spinal cord [41, 42]. SNRIs also elicit their effect through inhibition of NE and 5-HT blocking their role in descending pain pathways.

### **5. Cannabinoids**

The term cannabinoid is used to collectively describe all naturally occurring and synthetic compounds that are structurally similar to and elicit similar effects as the cannabinoid plants, most notably *cannabis*. In addition to the cannabinoids derived from plants (phytocannabinoids), there are also endogenously produced cannabinoids (endocannabinoids) and synthetic cannabinoids now being produced for medical use. Endocannabinoids are fundamental in human homeostasis with established behavioral, metabolic, immunologic, and physiologic functions [43]. Cannabinoids bind to two isotypes of G protein coupled receptors, CB1 and CB2 [44]. The CB1 receptor is found predominantly in the CNS including the brain, spinal cord, and the sensory nerve terminals and along primary pain pathways. Activation of CB1 receptors at these sites results in membrane hyperpolarization and the modulation of nociceptive neurotransmitters contributing to both the pain relief and psychotomimetic properties of cannabinoids [45]. This reduced pain with cannabinoid receptor agonists can occur at multiple levels of the CNS both peripherally and centrally. CB2 receptors are concentrated in the hematopoietic cells of the immune system and are involved in a diverse range of immunomodulatory effects including the inhibition of cytokine release [46, 47].

Cannabis contains over 500 chemical compounds including over 150 phytocannabinoids with the most studied being Δ<sup>9</sup> -tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the chief psychotropic compound of *cannabis* and is found in varying concentrations in different strains of the plant. THC has a strong affinity for CB1, which is regarded as the primary receptor responsible for the psychoactive effects seen with cannabis. In contrast, CBD does not activate CB1 so it does not produce psychoactive effects and is associated more with the anti-inflammatory effects of cannabinoids [48]. There are currently three cannabinoid drugs available for use in the United States. Epidolex® is a CBD based drug used to treat epileptic disorders and is derived from cannabis. Dronabinol and Nabilone are synthetic THC compounds approved for use in chemotherapy associated nausea and as an appetite stimulant in HIV/AIDS [49]. Molecular and preclinical evidence continues to support the anti-nociceptive properties of cannabinoids although experimental human studies are more heterogeneous with varying results although ongoing research is being conducted [50]. With major legislative changes in the USA, thirty-three states and the District of Columbia have passed laws broadly legalizing cannabis in some form at the time of this writing.

**265**

that arise with their use.

used in the management of neuropathic disorders.

*NSAIDs, Opioids, and Beyond*

**6. Ketamine**

**7. Conclusions**

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

antihyperalgesia and induction of anesthesia [54].

Ketamine is a dissociative analgesic and amnestic medication that acts as a non-competitive antagonist of the N-Methyl-D-Aspartate (NMDA) receptor in the central nervous system [51]. It has been used since the 1960s as an anesthetic agent and continues to be studied and adapted for novel psychiatric and anesthetic purposes. Ketamine has multiple sites of drug action but its principal nociceptive effects occur at the NMDA receptors. NMDA receptors have dense expression in the temporal cortex, hippocampus, basal ganglia, cerebellum and brain stem and are known to contribute to the neuronal process that mediate nociception via activation by glutamate, an excitatory amino acid [52]. By targeting this receptor, ketamine has profound attenuating effects on ascending nociceptive transmission and amplification of descending inhibitory pathways [52, 53]. Ketamine is currently utilized in the management of many diseases and other applications including the management of chronic pain disorders (e.g., complex regional pain syndrome, phantom limb pain, fibromyalgia), acute pain, conscious sedation, and intraoperatively for

NSAIDs have been used historically to treat both acute and chronic pain. They

Opioids remain a popular option in treating pain due to their effect on the Mu (μ), Delta (δ), and Kappa (κ) receptors. By activating these receptors, opioids can prevent the release of pain-promoting neurotransmitters providing their analgesic effects. However, the activation of the same receptors is also responsible for the associated side effects. These side effects vary depending on either acute or chronic use but can be life-threatening in some cases. This includes respiratory depression which can lead to fatal apnea. Chronic opioid use is associated with opioid induced constipation that can cause significant morbidity. It is therefore recommended to include prophylactic laxatives with chronic regimens. It is important to remember that addiction and tolerance is associated with opioid use due to its euphoric effect. Therefore, the clinical use of these medications should not only depend on their mechanism of action but also on understanding the potential severe complications

Neuropathic chronic pain disorders have been effectively treated with antidepressants. These disorders include, but are not limited to, diabetic peripheral neuropathy, HIV polyneuropathy, and post-herpetic neuralgia. One of the first line options are the tricyclic antidepressants (TCAs) which are usually started and maintained at lower doses versus the depression doses. This helps reduce some of their side effects including urinary retention, sedation, and dry mouth. Other antidepressants include serotonin-norepinephrine reuptake inhibitors that are also

possess analgesic, antipyretic, and anti-inflammatory properties through the inhibition of the pro-inflammatory cyclooxygenase (COX) enzymes. Their mechanism of action allows them to establish efficacy in treating a variety of pain diseases but also allows their routine use to produce serious side effects. COX-1 receptors are expressed throughout our body and its inhibition can lead to gastric mucosal injury including gastroduodenal ulcers. Selective COX-2 inhibitors were created with hopes of avoiding the side effects connected with non-selective COX-inhibitors; however, they are associated with their own complications which include an increased risk for cardiovascular events (thrombosis and hypertension).
