#35270: Multimodal Pharmacotherapy for Pain Management

Action potentials are changes in polarity along a nerve based on ion flow into and out of the nerve cell. As the action potential travels down the length of the cell, it will end at a point in the nervous system that results in some form of output, either physical (muscle movement) or experiential (pain). Figure 2 shows some of the details of an action potential and provides an extended explanation of their formation. Of particular importance is the quantity of ions moving at any specific time. The primary ions moving after stimulation and reaching threshold are Na+ (sodium, into the cell), K+ (potassium, out of the cell), and Cl- (chloride, into the cell). After the nerve has fired, the sodium/potassium adenosine triphosphate (ATP)-ase pump works to move sodium out of the cell and potassium back into the cell. A pump is needed because the ions are moving against their gradients, and energy is required in the form of ATP to power the pump.

ION MOVEMENT IN ACTION POTENTIAL FORMATION

Point A above shows the resting membrane potential of the nerve. At rest, a certain degree of leakage of both the sodium (Na+) into the cell and potassium (K+) out of the cell occurs. When a painful stimulus is experienced in the periphery, impulses will arrive at some point along a secondary nerve. Note the gradual upslope of the potential within the cell (the section between points A and B). In this example, painful impulses are coming into a section of nerve tissue from a free nerve ending, resulting in opening voltage-gated Na+ channels, resulting in an influx of Na+ that is faster than the outward leakage of K+, leading to an increasing membrane potential. Once membrane potential reaches threshold (point B), a large number of voltage-gated Na+ channels open, resulting in a large shift of Na+ ions from the extracellular fluid to the intracellular fluid, causing the initiation of an action potential (shaded area 1). Voltage-gated K+ and chloride (Cl-) channels then open, allowing K+ efflux and Cl- influx, dropping membrane potential (shaded area 2). The movement of K+ and Cl- is so great that an overshoot occurs, and the nerve hyperpolarizes (or falls below resting membrane potential, point D and shaded area 3). The Na+/K+ ATP-ase pump begins to work (shaded area 3) and equalizes Na+ and K+ gradients to result in a return to normal resting membrane potential.

Figure 2

Source: [7]

A variable but set amount of nervous action potential impulses is required to reach threshold. The nerve must receive a sufficient number of input signals (or stimuli) to move its membrane potential above threshold and fire an impulse, sending, in this case, a message of pain along a nerve pathway. Understanding the science behind the action potential and its formation is crucial for the healthcare provider, as many analgesic drugs work by altering the transmissibility of signals sent along the nerve. If the action potential formed in the FNE can be blocked or altered, painful sensations can be mitigated or eliminated.

The FNEs are one of the sets of tissue receptors that can be stimulated to send impulses (action potentials) along the length of the nerve for further interpretation either in the spinal cord or various sections of the brain. Despite the study of FNEs over the past decade, the exact mechanism of action is still unknown. There are several postulations about how stimuli cause the firing of FNEs, initiating action potentials and resulting in the experience of pain. FNEs are also referred to as nociceptors. While nociceptors are often described as pain receptors, the purpose of the nociceptor is to alert the body to the presence of tissue damage [8]. FNEs are small structures, with a thin layer of Schwann cells surrounding them. They are branched in appearance and have small varicosities containing mitochondria, vesicles, and an axonal reticulum (analogous to the sarcoplasmic reticulum or endoplasmic reticulum in other cell types) [5,9]. The vesicles contain numerous neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), both of which are crucial in spreading action potentials during conditions of tissue destruction resulting in pain [9]. Figure 2 illustrates varicosities in the distal ends of the FNE, but these structures are present throughout the FNEs until they reach larger nerves.

There are two primary types of nerves that carry pain data elicited by stimulation of an FNE: type Aδ or myelinated (fast) nerve fibers and type C or unmyelinated (slow) nerve fibers [5,8]. Myelinated fibers are insulated with Schwann cells, but with gaps (nodes of Ranvier) in which the nerve fiber is exposed to the environment of the extracellular fluid. The myelinated fibers are also referred to as fast fibers because the action potentials can skip between the nodes of Ranvier in a process called saltatory conduction (rather than traveling the entire length of the axon). Sharp or acute pain, especially from traumatic injury, is usually processed in this fashion.

Type C fibers move impulses more slowly. While myelinated fibers can carry action potential impulses at speeds of 5–30 meters per second, unmyelinated fibers have speeds of 0.4–1.4 meters per second [8]. Most individuals have experienced this type of pain differential speed in their own lives: an acute accidental injury such as cutting one's finger while cooking results in an immediate response followed by an aching sensation. This is because both type A and type C nerve fibers travel in bundles together, and the stimulation of one nerve makes the stimulation of a nearby nerve easier. An example of this phenomenon is seen in Figure 3. The solid line represents an unmyelinated nerve (type C), while the line with nodes represents a myelinated nerve (type Aδ). If the nerves travel together from the site of injury, the patient experiences two waves of pain. Myelinated fibers carrying information about pain tend to be highly localized, dependent on the density of FNEs in the area of injury. Unmyelinated fibers tend to carry information related to aching or less acute or localized pain. A significant amount of visceral pain tends to be carried by unmyelinated fibers, making diagnoses of this type of pain difficult.

SIMPLIFIED PAIN PATHWAY

Figure 3

Source: Bettina Guebeli, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

Pain pathways are complex routes over which action potentials are sent from the peripheral nerves to the central nervous system (CNS). An interruption of the pathway at any point tends to mitigate the degree of pain felt by the patient and, in some cases, may alleviate pain entirely. This can be accomplished by blocking some part of the pathway with a local anesthetic or by administering an agent(s) that drives the resting membrane potentials of neurons in a more negative fashion or interrupts the pathway within the brain. One of the key aspects of multimodal pharmacologic pain relief is to use smaller doses of various agents that work at different points along the pathway, minimizing adverse side effects while maximizing the number of sites of action.

Pain and other impulses originate in the peripheral nervous system (PNS), enter the dorsal horn of the vertebra, and then ascend to the brain along the spinothalamic tract. This is a three-neuron pathway containing first-, second-, and third-order neurons. In Figure 4, the spinothalamic tract can be traced from the primary afferent nerve (receiving the pain signals at the site of injury) to the spinal cord, entering via the dorsal root of the cord. At this point, the first-order neuron synapses with a second-order neuron. Upon entry into the cord, the second-order neuron crosses from the right to the left (or left to right, if it enters the left dorsal root). This is referred to as decussation. The second-order neuron then rises up the cord in either the anterior or later spinothalamic tract, synapsing with a third-order neuron in the thalamus. This neuron leads to the sensory cortex in the brain, which in turn interprets the exact location and degree of pain.

FAST VS. SLOW PAIN TRANSMISSION

Figure 4

Source: Bettina Guebeli, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

Complex Ascending Pain Pathways

Figure 5 is a complex diagram of the ascending pain pathways. Starting in the lower left corner (with the stimulus), the pain pathway can be seen tracking along both Ad and C fibers and entering the dorsal root of the spinal cord. The peripheral nerve synapses with a second-order nerve (Box 1) that decussates across the spinal cord; activating or inhibiting the interneurons in the lamina of the dorsal root can stop the impulse from propagating. The pain pathway then begins to ascend the anterior and lateral spinothalamic tracts toward the brain (Box 2). In the neck area of the diagram, the spinothalamic tract has been highlighted (Box 3), and it continues to ascend into the thalamus in the brain. The second-order neurons synapse in a special area of the thalamus called the ventrobasal complex (Box 4) [5]. The thalamus, when activated, is thought to cause the conscious perception of pain and provides an anatomic location for the cell bodies of the third-order neurons [5]. The third-order neurons then ascend to the somatosensory cortex, allowing the patient to localize and quantify the painful stimulus (Box 5).

ASCENDING PAIN PATHWAYS

This is a cross-sectional view looking from the top of the head down toward the feet. As indicated by the box labeled abdomen, the patient is lying face down.

Figure 5

Source: Richard Lennertz, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

The thalamus also has neuronal branches that help to stimulate the reticular activating system, the portion of the brain responsible for sleep and waking [5]. The thalamus has numerous projections into other areas of the brain, including the prefrontal cortex and the amygdala, the latter of which is part of the limbic system [16,17]. The projections of the neurons into the limbic system account for the suffering aspect of pain, where the sensation is overlaid with an emotional experience. As pain is important in preventing homeostasis damage, including an emotional response to pain (in addition to a sensory response) helps ensure the person experiencing pain will avoid the stimulus that led to the pain.

The hippocampus is another area that receives neuronal impulses during painful stimuli [17]. Previous studies have linked decreases in hippocampal volume to major depression; however, the hippocampus also helps process and modify nociceptive stimulation [18,19]. Further, the hippocampus is the primary site for implanting memories [17].

Patients who are exposed to chronic pain or chronic stress may develop severe pain syndromes refractory to usual treatment. These pain syndromes have been associated with increased production of tumor necrosis factor-alpha (TNFα), a proinflammatory cytokine that sensitizes the patient to increased levels of pain secondary to local inflammation [19]. These inflammatory processes also atrophy the hippocampus, which has been associated with major depressive disorder [20]. It is not unusual, therefore, for unremitted or inadequately treated pain to co-occur with severe depressive disorders [21,22].

Pain pathways stimulate many areas of the brain. The brain responds by the release of many neurotransmitters and other hormones to provide a systemic response [10]. As discussed, pain impulses activate the amygdala, which triggers a sympathetic nervous system response, sometimes referred to as the "fight-or-flight" response. The release of norepinephrine and epinephrine results in, among other things, tachycardia, hypertension, and elevated blood glucose levels. Additionally, the local response to the stimulus produces the release of local neurotransmitters, such as substance P, glutamate, CGRP, and brain-derived neurotrophic factor (BDNF) [10,11]. Of perhaps greater concern is the release of cytokines, which results in a profound inflammatory response. The inflammatory response is usually highlighted by hyperalgesia (exaggerated painful response to a painful stimulus) and allodynia (painful response from a non-pain-inducing stimulus). Take the example of a minor sunburn. If the skin is reddened and inflamed, a pat on the back becomes inordinately painful (hyperalgesia) and simply wearing a shirt may be intolerable (allodynia). In addition to these responses, untreated acute pain may lead to the expression of additional FNEs and nociceptors.

Acute pain usually has an easily recognized proximate cause and can be well-localized. The possible exception is intra-abdominal or pelvic pain, in which unmyelinated nerves are responsible for most nerve impulse propagation. However, even this hard-to-localize pain is often characterized to a general area ("My stomach hurts") rather than being poorly defined ("Everything aches").

In some cases, acute pain is associated with a medical procedure, such as routine surgery. For these patients, it is possible to visualize precisely where tissues have been manipulated and thus the location of the pain. The advantage of treating this form of acute pain is that treatment can be pre-emptive, with the administration of analgesics as part of the overall management plan [27].

Chronic pain is experienced by nearly one-third of the adult population of the United States and is associated with costs of more than $600 billion per year [11]. It can result in physical and emotional disability. It has become clear that chronic pain is far different from acute pain in its experience and treatment. While acute pain is related to a specific injury site, chronic pain is often centrally mediated and can therefore occur without the stimulation of a peripheral nerve [7,11,28]. Unfortunately, while acute pain can serve some adaptive purpose in protecting the person from harm, chronic pain is maladaptive in nature and typically has no beneficial biologic or systemic significance [11].

Historically, the initial approach to diagnosis and management of pain emphasized the identification of disease, lesion, or anatomic site of the pain, without reference to the underlying neural mechanisms or the application of this to treatment considerations [29]. Evidence now strongly supports combining the conventional etiology-based approach with a mechanism-based approach that classifies pain syndromes by the type of maladaptive nervous system alteration that has developed in reaction to the original insult. This approach provides a comprehensive dual therapeutic focus that targets the pathologic sustaining mechanism of the pain as well as the original disease, lesion, or tissue injury that has been the traditional focus of pain management [29,30]. Such an approach is believed to optimize pain diagnosis and treatment by avoiding the limitations associated with the traditional etiology-based approach [31,32,33,34,35,36].

Most pain syndromes involve multiple, often overlapping, neurobiologic mechanisms determined by the stage of the disease process. Current concepts of pain classify these into four main categories: nociceptive, inflammatory, neuropathic, and centralized [37].

Nociceptive pain is a physiologic response to tissue injury, the perception that arises from intense stimulation of specialized peripheral sensory neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is subgrouped by location of involved tissues into somatic pain (muscle or connective tissue) and visceral pain (visceral structures) [38]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and pathologic when it persists after healing has occurred.

Inflammatory pain occurs in response to tissue injury or infection that activates peripheral nociceptors and initiates the immune response. While the resultant production and recruitment of pro-inflammatory mediators to the injury site may serve to perpetuate discomfort, it also facilitates tissue repair; thus, this is considered an adaptive pain mechanism.

Neuropathic pain originates from peripheral or central nervous system injury. Unlike nociceptive and inflammatory pain, the mechanism of neuropathic pain has no adaptive function and is strictly pathologic [32,39]. Acute pain from somatosensory damage is termed "acute neural injury." The term "neuropathic pain" implies pain that persists beyond the period of expected or actual tissue healing, and the underlying mechanism involves a maladaptive alteration in somatosensory nervous system function [35].

Centralized pain results from heightened nociceptive sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral inflammatory pathology. The mechanism is poorly understood and is regarded as strictly pathologic as it lacks any evident adaptive function. Centralized pain disorders include conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [32,38,40].

The persistence of acute nociceptive, inflammatory, or neural injury pain beyond tissue healing or repair reflects ongoing nociceptive activity that has become dissociated from peripheral nociceptive input to become maladaptive. Regardless of whether acute pain originates from tissue injury, tissue infection, or peripheral nerve injury, a similar process occurs by which nociceptive, inflammatory, and neuropathic pain signals are relayed from tissue injury site to the brain. This highly intense or prolonged pain signaling can lead to profound alteration in neuronal pathways that are further "upstream" from the peripheral tissue pain origin. Among these are increased ascending pathway signaling to the brain, reduced descending inhibitory signaling, expansion of pain receptive field, and induction of spontaneous and widespread pain. The resulting peripheral and central pathway hypersensitivity represents a state of abnormal nervous system function, amplified central nervous system sensory signaling, and abnormally low threshold pain response. The pain is no longer a symptom of peripheral insult, but a disease state of the nervous system [35]. This transition from acute to chronic pain occurs in discrete pathophysiologic steps involving multiple signaling pathways [41].

According to the Institute for Clinical Systems Improvement, there needs to be shared decision-making with the patient about reducing or eliminating opioids to avoid unnecessary complications from long-term opioid use. This involves following and re-evaluating the patient closely, with dose reduction or discontinuation as needed.

(https://www.icsi.org/wp-content/uploads/2020/01/PalliativeCare_6th-Ed_2020_v2.pdf Last Accessed: October 20, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Opioid analgesics produce therapeutic and side effects by mimicking endogenous opioid activity, although some opioids produce analgesia by activity outside the opioid receptor complex. Opioids widely differ in levels of affinity and activation of opioid receptor subtypes. In addition, inter-individual variation in analgesic response and side effects is significant, largely driven by genetic factors [42]. The complex interaction between unique opioid properties and individual patient characteristics dictates that a patient-tailored approach is required for opioid selection, dose initiation, and titration to optimize safety, analgesia, and tolerability.

Naturally occurring opioid compounds are produced in plants (e.g., opium, morphine) and in the body (the endogenous opioids) [43]. Endogenous opioids are peptides that bind opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone secretion, thermoregulation, and cardiovascular function. The three primary endogenous opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three primary opioid receptor types are mu, kappa, and delta [44,45]. A quick overview of this complex pain modulation system is helpful in understanding how opioid analgesics work.

NSAIDs alleviate pain by inhibiting the conversion of arachidonic acid to prostaglandins catalyzed by COX isozymes. Nonselective NSAIDs inhibit COX-1 and COX-2 and include ibuprofen, aspirin, and naproxen. The nonselective action inhibits the formation of both gastroprotective-mediating prostaglandins and pain-promoting prostaglandins, increasing the risk of serious toxicities such as GI ulceration and bleeding. This prompted the development of selective COX-2 inhibitors, which produce fewer GI side effects but are linked with an increased risk of cardio-renal morbidities [71]. To mitigate risk of GI adverse events, proton pump inhibitors are recommended for use in some patients using NSAIDs [72].

Acetaminophen is available over the counter and is also included in combination with many prescription opioids. Analgesia is achieved through central but not peripheral inhibition of prostaglandin. Although effective in mild pain, acetaminophen is not anti-inflammatory. The side-effect profile is relatively benign with intermittent use at recommended labeled dosing, but long-term or high-dose use can be hepatotoxic, and the daily dose should never exceed 4 g. Acetaminophen is recommended over NSAIDs as an analgesic in patients with GI, renal, or cardiovascular comorbidity [73].

While beneficial in the management of pain, some patients with reactive airway disease may develop bronchospasm, although this adverse effect is rare [5]. In addition, prostaglandins are vasodilators. A constitutive level of circulating prostaglandin is necessary to maintain adequate vasodilation in the afferent limb of the glomerulus to assure renal blood flow in the kidney. Overuse of NSAIDs may result in decreased glomerular blood flow, resulting in decreased elimination of toxins from the body and, in especially severe states, renal failure [5]. The most commonly used NSAIDs are listed in Table 4 [74,75].

Local anesthetics prevent the generation and propagation of nerve impulses in response to painful stimuli. The basic chemical structure of a local anesthetic consists of an aromatic ring (which enhances lipid solubility) and an intermediate ester or an amide chain and a terminal amine [8]. As such, all of these agents are classified as either an ester type or an amide type. The type of anesthetic used and the inclusion of a vasoconstrictor (e.g., epinephrine) will influence the duration of action. Certain factors, such as the presence of active infection in the area to be anesthetized, heightened patient anxiety, or inaccurate deposition of the agent, may affect the ability of a local anesthetic to achieve the appropriate level of anesthesia.

The local anesthetics lidocaine and bupivacaine block Na+ influx of voltage-gated ion channels in afferent neuron terminals, inhibiting depolarization and generation of action potentials, resulting in the transmission of fewer nociceptive impulses to the spinal cord. In clinical application, topical lidocaine is used for neuropathic pain to block hyperactive sodium ions in damaged peripheral nerves and inhibit transmission of ectopic impulses to the dorsal horn. This action interferes with peripheral and central sensitization and maladaptive neuroplasticity [71,76].

Capsaicin defunctionalizes nerve fiber terminals through multiple mechanisms to produce analgesia. The initial reduction in neuronal excitability and responsiveness result from inactivation of voltage-gated sodium channels and direct desensitization of plasma membrane TRPV1 receptors. This is followed by extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm the TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [77,78]. The persistent effect involves extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [77,78]. Capsaicin is available as a high-potency (8%) patch and as a lower-concentration cream. A single 60-minute application may provide up to 12 weeks of analgesia [76]. Capsaicin may initially cause pain because substance P is released from nociceptive terminals to initiate nociceptive firing. The analgesic response follows as nociceptive terminals desensitize to elevate pain threshold [79].

The use of local anesthesia has become more popular and may be more precisely administered being guided by ultrasonography. Ultrasound technology allows for optimized needle placement, resulting in fewer failed blocks and lower doses. These blocks can be performed before having a procedure performed. When administered before surgery, local anesthetic blocks allow for lower doses of anesthetic agent, along with prolonged postoperative pain relief. In one study, when a local anesthetic block was provided in addition typical analgesic therapy following total knee replacement, morphine doses, pain scores, and nausea were all significantly decreased compared with those who received usual treatment [80].

However, local anesthetics are not without drawbacks, and overdose resulting in local anesthetic systemic toxicity (LAST) is a concern [81]. Because local anesthetics are designed to cross phospholipid membranes, they easily enter the brain and heart, where the blockade of ion channels can have adverse effects. Normally, the first symptoms in patients who are conscious are a metallic taste and/or ringing in their ears (tinnitus). If left untreated, this can progress to excitatory symptoms, followed by drowsiness, coma, and even death [81,82]. Table 5 provides key information about commonly used local anesthetics, including maximum doses.

The closer to the vasculature the site of injection is, the more likely that the local anesthetic will undergo rapid vascular uptake and result in adverse effects. Mixing the agent with epinephrine, a vasoconstrictor, decreases uptake, thus prolonging the anesthetic effect and decreasing the likelihood of complications. As this is the case, it is possible to give more local anesthetic when it is mixed with epinephrine [82,83,84].

In the event of an accidental overdose, there is a specific protocol for treatment [81,82]. As soon as LAST is detected, the patient should be administered an IV bolus injection of 20% lipid emulsion 1.5 mL/kg-1 over one minute. An infusion of 20% lipid emulsion should be started at a dose of 15 mL/kg-1/hour. If after five minutes cardiovascular stability is not restored or the patient further deteriorates, a maximum of two repeat boluses may be administered, with five minutes between injections. At the same time, the infusion rate may be doubled. The infusion should continue until the patient has stabilized or the maximum dose of emulsion (12 mL/kg-1) has been given. The use of lipids to rescue these patients is a relatively new development, so review is important for those in clinical areas with high use of local anesthetics [85].

The gabapentinoids, gabapentin and pregabalin, are widely used in the management of both postoperative and chronic pain relief. Their names may give the impression they interact with gamma-amino butyric acid (GABA), but this is not the case [86,87]. Gabapentin and pregabalin are anticonvulsants that are also effective in a wide range of neuropathic pain conditions. Their mechanism of action involves selective binding to and blockade of the α2δ1 subunit of voltage-gated calcium channel in various brain regions and the superficial dorsal spine. This inhibits the release of glutamate, norepinephrine, and substance P to decrease spinal cord levels of neurotransmitters and neuropeptides [76,88,89]. The binding affinity of pregabalin for the calcium channel α2δ1 subunit is six times greater than gabapentin, which is reflected in the greater efficacy of pregabalin at lower doses. Because gabapentin possesses a shorter half-life and nonlinear absorption, pregabalin is easier to titrate and better tolerated [89].

While having a long history in the treatment of chronic pain, the use of these agents to prevent postsurgical pain is relatively new. In one study of 90 women scheduled for abdominal hysterectomy, a control group was compared to groups receiving either 300 mg pregabalin or 900 mg gabapentin administered one to two hours prior to surgery [86]. The average time until first request for analgesia was 31 minutes in the pregabalin group, 16 minutes in the gabapentin group, and 7 minutes in the control group. There was no difference in demographic variables, including length of surgery, across the three groups. In this case, preoperative administration of a gabapentinoid was shown effective in lengthening the duration of analgesia [86].

The locus coeruleus is activated during normal responses to painful stimuli. However, in patients with chronic pain, stimuli inhibit rather than activating the locus coeruleus, dampening analgesic response [90]. When gabapentin is administered to these patients, glutamate is released in the brain, which in turn stimulates the locus coeruleus, restoring its analgesic function [91].

While more commonly associated with the autonomic nervous system and its functions, alpha-adrenergic agonists can also function in the relief of pain, as well as decreasing the sympathetic side effects which accompany pain, including hypertension and tachycardia. Antinociceptive activity of the α-2 adrenoceptor agonists clonidine and tizanidine includes modulating dorsal horn neuron function and norepinephrine and 5-HT release, potentiating mu-opioid receptors, and decreasing neuron excitability through calcium channel modulation [92]. Clonidine is available as a transdermal patch for use in neuropathic pain states. Local use enhances release of endogenous enkephalin-like substances. Intrathecal or epidural administration with opioids and/or local anesthetics is favored in treating neuropathic pain because the synergistic effect improves pain control. Tizanidine is used as a muscle relaxant and antispasticity agent; its use in the management of musculoskeletal pain is off label [76,79].

Dexmedetomidine was originally approved as a short-term sedative analgesic for mechanically ventilated patients in the intensive care unit [93]. Dexmedetomidine is far more selective as an alpha-adrenergic agonist and has the same central action around the locus coeruleus [93]. As time passed since its introduction, the use of dexmedetomidine has increased, especially among patients with comorbidities (e.g., heart and vascular disease, morbid obesity). Its cardiovascular stability, along with its minimal effect on respiratory drive after the infusion is terminated, have made this agent popular in both the intensive care unit and the operating room. Aside from its use as a sedative or aesthetic agent, use of dexmedetomidine has been explored in patients with refractory end-of-life pain. In a case study, a male patient, 58 years of age, with chronic pancreatitis secondary to alcoholism reported inadequate pain relief despite receiving a combination of oxycodone, nortriptyline, and lorazepam. Increased inpatient intravenous opioids and ketamine still brought the patient no relief, and dexmedetomidine was attempted as a last resort. An infusion of dexmedetomidine brought the patient's pain under greater control, to the extent that he was able to sit in a recliner and visit with family [94]. Based on this and other reports, dexmedetomidine is being explored as a possible option in palliative care.

Alpha-adrenergic agonists are also found in the area of the brain where projections from the locus coeruleus inhibit an inhibitory portion of the brain responsible for arousal. When alpha-adrenergic agonists act in this area of the brain, they block the ability of the nerves projecting from the locus coeruleus to inhibit the second-order neuron. Thus, these agents, in sufficient doses, render the patient somewhat drowsy [95]. This is important to remember, as the drowsiness associated with the original alpha-adrenergic agonists made their use problematic.

Anesthetics are powerful agents typically used in the operating room to reduce the capacity for consciousness and diminish the pain associated with surgery. Two examples are ketamine and nitrous oxide. These agents are quite different; the first is an injectable dissociative anesthetic with variable effects depending on the dose, and the second is an inhaled vapor with profound analgesic effects [18,96,97].

Ketamine

Ketamine is a phencyclidine anesthetic given parenterally, neuraxially, nasally, transdermally or orally in subanesthetic doses to alleviate a variety of pain conditions, including severe acute pain, chronic or neuropathic pain, and opioid tolerance [79]. The mechanism of analgesic effect primarily involves NMDA receptor inhibition. Thus, patients with NMDA-mediated central sensitization are likely to realize significant benefit from treatment with ketamine. Ketamine also has activity on nicotinic, muscarinic, and opioid receptors and exerts both anti-nociceptive and anti-hyperalgesic effects, with the latter produced at lower dose ranges [98].

The American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists recommend that subanesthetic ketamine infusions be considered for patients undergoing painful surgery and patients undergoing surgery who are opioid-dependent or opioid-tolerant.

(https://rapm.bmj.com/content/rapm/43/5/456.full.pdf Last Accessed: October 20, 2022)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.)

Ketamine is one of very few therapies demonstrating substantial and durable pain reduction of treatment-refractory chronic regional pain syndrome [99]. Potentially distressing adverse reactions (e.g., hallucinations, disturbing dreams, out-of-body experiences) and unwanted changes in mood, perception, and intellectual performance have limited its clinical use in pain control. However, trials have effectively controlled these side effects with high-dose co-administration of midazolam or lorazepam combined with either clonidine or ondansetron [100,101].

Ketamine, however, also has its down sides. One of the most concerning is the formation of psychotomimetic behaviors, and the presence of hallucinatory phenomena after its administration. Fortunately, these are dose dependent in nature and rarely occur at the doses required to treat pain [102,103]. It has also become a drug of abuse and misuse. Most notoriously, ketamine became known as a "date-rape drug," because it was administered in drinks to unknowing victims who were subsequently sexually assaulted by their predators. Because ketamine causes amnesia, victims have little or no memory of what occurred to them, although they often experienced after-effects, such as pain. As a result of this growing criminal use, Congress passed the Drug-Induced Rape Prevention and Punishment Act of 1996. During this period and the decade following, there was increased awareness of the dangers of ketamine and other drugs that were used in a similar manner, such as flunitrazepam (Rohypnol) and gamma hydroxybutyric acid (GHB) [104]. As a result, ketamine developed a stigma, and this negative view may persist in many minds.

Today, ketamine is increasingly being used to treat patients with treatment-refractory major depressive disorder, which frequently co-occurs in those with chronic pain. The agent appears to actually increase the size and volume of the hippocampus, thus treating the cause of depression [18,105]. In patients who are imminently suicidal, short-duration doses have been found to significantly reduce suicidal ideation [106].

Antidepressants, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs), are now a mainstay of pain management. Each of these agents increases the circulating level of neurotransmitters (e.g., norepinephrine, serotonin, dopamine, acetylcholine) in the brain [111]. Note that while these agents have been used for pain management in some cases for decades, this use is often still considered to be off label [111].

Antidepressants act in the brain at the periaqueductal grey, the amygdala, the prefrontal cortex, the thalamus, and the somatosensory cortex, among other places [112]. However, they also work in the periphery, primarily by blocking voltage-gated Ca2+ channels, especially in the dorsal horn of the spinal cord. As discussed, when Ca2+ cannot enter a neuron, then exocytosis of neurotransmitters onto the receptors of the next order neuron cannot take place. This, in turn, blocks the transmission of the action potential and thus the painful stimulus [112]. Antidepressants also increase the effectiveness of endogenous GABA, an inhibitory neurotransmitter. The various antidepressant classes have different effects on pain pathways.

In one study, 150 patients were assessed for breakthrough pain following shoulder surgery [120]. The first group (75 patients) was given a standard course of opioid and acetaminophen combination (hydrocodone 10 mg/acetaminophen 325 mg) or 5–10 mg of oxycodone every 4 hours [120]. They also received a single-shot interscalene regional nerve block with 0.5% ropivacaine (local anesthetic). Finally, intravenous hydromorphone was also available as a rescue intervention. In the second multimodal group (75 patients), patients received preoperative 300 mg celecoxib, 600 mg gabapentin, and 1,000 mg acetaminophen. They also received the same regional nerve block. For postoperative pain, group 2 received naproxen 500 mg every 12 hours with food, gabapentin 300 mg every 8 hours, acetaminophen 1,000 mg orally or IV, followed by 500 mg orally every 6 hours. For breakthrough pain, this group could receive 5–10 mg of hydrocodone, as needed [120]. There were no differences in the demographic makeup of the two groups.

On postoperative day zero (the day of surgery), pain scores were significantly lower in group 2 when compared with the standard group [120]. On postoperative days 1 and 2, the multimodal group continued to have lower scores, but the differences were not statistically significant. Opioid consumption, measured in mg of morphine equivalent, were significantly decreased in the multimodal group on all three measurement days. The length of in-patient stay for the multimodal group was significantly lower (1.4 days +/- 0.7) compared with the opioid group (1.9 days +/- 1.1 days), resulting in an average cost savings of $1,000 for the multimodal group [120].

In this study, patients with unresectable hepatocellular carcinoma received transarterial chemoembolization, a primary palliative treatment [121]. This group of patients have chronic pain, and transarterial puncture is associated with a lower degree of surgical pain. In this example, patients are provided with a therapeutic procedure that can partially mitigate the pain and then supported with other analgesic agents. The study involved a total of 84 patients, with half assigned to the multimodal group and the other half assigned as a control group [121].

The multimodal group received 40 mg intravenous parecoxib sodium 30 minutes before the beginning of the procedure. In the control group, patients received 5 mg dezocine (an opioid) preintervention. All patients underwent a percutaneous puncture of the femoral artery after having the site numbed with 10 mL 2% lidocaine (total dose: 200 mg lidocaine). After the procedure, the multimodal group was provided with a patient-controlled analgesia pump; the intravenous pain solution was a combination of sufentanil 100 mcg and dexmedetomidine 200 mcg diluted in 100 mL normal saline. The pump was programmed to provide 2 mL of the solution (2 mcg of sufentanil and 4 mcg of dexmedetomidine) as a first dose, a background infusion rate of 2 mL/hour, and 2 mL bolus doses on demand with a lockout period of 5 minutes (maximum: about 12 doses per hour) [121]. This sufentanil dose is below the usual administered for general anesthesia. The dose of dexmedetomidine tracks closely to that needed for intensive care unit (ICU) sedation [122]. Using the two agents together provides central sedation via two routes (one from the opioid, the other from the alpha-2 agonist) while simultaneous providing pain relief throughout the spinal cord.

The control group received 100 mg flurbiprofen (an NSAID) every 12 hours for the first 48 hours postprocedure and 100 mg tramadol (a combination opioid agonist and SSRI) for breakthrough pain [121]. Mean visual analog scale (VAS) pain scores were measured at 0, 2, 4, 6, 12, 24, and 48 hours after the procedure. Patients in the multimodal group had statistically lower VAS pain scores at 0, 2, 4, 6, and 12 hours after the procedure. From a qualitative viewpoint, more than 95% of the multimodal patients reported good satisfaction with their pain control. In the control group, 69% reported good satisfaction, and 11.9% reported a "fairly bad experience" of pain control [121].

Note that this first example is directed toward the management of acute pain, and the interventions take place in the hospital or surgical facility. Many people, however, suffer chronic pain and self-medicate to treat it. In either case, multimodal analgesic techniques may still be used.

Patient A is scheduled to receive a total knee replacement arthroplasty [123]. Preoperatively, the patient is counseled regarding what pain might be expected with this surgery and how it might be treated. After the patient has been worked up, she receives acetaminophen 1,000 mg and celecoxib 400 mg by mouth [123]. This is referred to as pre-emptive analgesia and is done to ensure that the processes needed to, in this case, block the inflammatory effects of prostaglandins released by surgery are beginning to function prior to initiation of surgery [124].

The patient is next taken to a block room and receives local anesthesia in the knee area. In other cases, surgeons may inject local anesthesia at the end of the case.

During surgery, the patient receives a spinal anesthetic with local anesthesia. The anesthetic is placed in the subarachnoid space with local anesthesia. Because the local anesthetic is deposited so close to the nerves, a very small dose can provide several hours of anesthesia.

After surgery, the patient begins to receive several pain management interventions almost immediately, the first of which is cryotherapy. Next, as the body is responding with an inflammatory process releasing prostaglandins and other neurotransmitters in response to an injury (albeit a therapeutic one), the patient receives 1,000 mg of acetaminophen every six hours around the clock [123]. This patient tolerated oral analgesics, but acetaminophen can be administered intravenously for those experiencing problems with postoperative nausea and vomiting. The patient is also started on celecoxib 200 mg twice per day for up to five days. At this point, Patient A begins to question the need for NSAIDs when she is "having no pain." The nurse describes the importance of reducing inflammation in simple terms. He also explains that the long-acting local anesthetics will wear off over time, and it is important to pre-emptively control pain. Despite these interventions, some patients will experience postoperative pain exceeding the ability of NSAIDs to mitigate. For these individuals, an opioid rescue (oxycodone tablet 5 mg and intravenous hydromorphone 0.2 mg) every four hours as needed will help bring most pain under control [123].

Patient B is an elderly man (85 years of age) with chronic and unremitting pain. Initial assessment of the patient's pain remains important. While Patient B is experiencing chronic pain, he may also have an unresolved injury or illness causing the pain. In such a case, treatment of the underlying pathology could result in mitigation of pain [125].

Therapeutic intervention for Patient B begins with the use of NSAIDs and COX-2 inhibitors, especially for a pathology such as osteoarthritis, which is quite common among the elderly. As part of the assessment in this example, remember that elderly patients tend to have less total body water, decreased muscle tone, increased fat stores, and normal age-related degeneration of the liver and kidneys [125]. Unless there are other factors (e.g., current opioid use disorder), the best approach is to start low and titrate slow—use the smallest dose possible and increase it incrementally in small doses. The elderly often experience depression as part of their chronic pain; this should not be surprising, as living with unresolved pain each day can be psychologically taxing. Antidepressant agents, such as an SNRI, may be added to the care plan, with the caveat that there is an increased risk of falling [126]. Gabapentinoids may replace the antidepressant if the pain is neuropathic in nature, and opioids can be added on an as needed basis, though it is crucial to start at the low end of the dosing scale [126]. This follows the WHO guidance of NSAIDs first and opioids last.

While it is fine to conduct mental exercises with imaginary patients, the guiding standard for the clinician is whether the analgesia works. This is an important question, so at this point a small number of studies will be presented for your review.

In this example, Patient C, a man 71 years of age, presents with a severe case of recurring right sciatic pain [127]. On history and examination, the patient describes persistent pain at a scale of 8 out of 10, starting in the lumbar area of his back and running down his right thigh. Further comorbidities include chronic obstructive pulmonary disease (COPD) and previous right-side neck surgery to remove a buccal tumor. An MRI is ordered, revealing spondylolisthesis, which causes pain in lower back or legs at L5–S1, and the patient was also identified as having degenerative disk disease at L5–S1, and disk herniations at L3–L4, L4–L5, and L5–S1 [127]. This patient is taking 20 mg oxycodone daily in an effort to mitigate his pain.

The pain control team begins to titrate back the patient's oxycodone with tramadol and offers surgical decompression. After the patient refuses surgical intervention, the team decides to administer an ultrasound-guided caudal epidural steroid injection of triamcinolone 40 mg and 2% lidocaine 20 mg (local anesthetic) mixed in 12 mL of normal saline [127]. The mixture of normal saline is necessary because epidural injections require a greater volume to ensure the nerve roots are all bathed in the solution.

After the injection, Patient C's walking distance increases from 20 meters to 200 meters, and his pain score reduces from 10 to 7. One month later, the patient remains improved, but the team decides to add 5 mg oxycodone (25% of the original dose) as needed back to the patient's regimen. By his third month post procedure, the patient's pain score has dropped to 2. The multimodal plan, when compared with the singular large dose opioid plan, proved to be life-changing for this patient [127].