# Internal Medicine/Pain
## Pain-Sensory System

Pain refers to an uncomfortable sensation localized in a specific part of the body. It is frequently described in terms of a penetrating or tissue-damaging process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Additionally, pain of moderate or higher intensity is accompanied by anxiety and a desire to escape or terminate the sensation. These properties demonstrate that pain has a dual nature: it encompasses both sensation and emotion. In its acute form, pain is typically linked to increased alertness and a stress response, which includes elevated blood pressure, heart rate, pupil dilation, and plasma cortisol levels. Moreover, local muscle contractions (e.g., limb flexion, abdominal wall rigidity) are often observed.

## Peripheral mechanism

A peripheral nerve consists of axons from three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons. Primary sensory afferents have their cell bodies located in the dorsal root ganglia within the vertebral foramina. These afferents have two branches, one projecting into the spinal cord and the other extending to innervate peripheral tissues. They are categorized based on their diameter, degree of myelination, and conduction speed. The largest-diameter afferent fibers, known as A-beta (Aβ), are most sensitive to light touch or moving stimuli and are primarily found in skin-innervating nerves. In normal circumstances, the activity of these fibers does not induce pain.
There are two other types of primary afferent nerve fibers: small-diameter myelinated A-delta (Aδ) and unmyelinated (C) axons. These fibers are present in nerves supplying the skin as well as deep somatic and visceral structures. Most Aδ and C fiber afferents respond intensely to noxious (painful) stimuli, causing the subjective experience of pain when activated. This identifies them as primary afferent nociceptors or pain receptors. Blocking conduction in Aδ and C fiber axons completely eliminates the ability to detect painful stimuli.
Individual primary afferent nociceptors can respond to various types of noxious stimuli, including heat, intense cold, intense mechanical distortion (e.g., pinching), changes in pH (especially acidity), and the application of chemical irritants like adenosine triphosphate (ATP), serotonin, bradykinin (BK), and histamine. The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the vanilloid receptor, plays a role in detecting certain noxious stimuli, especially heat sensations, and is activated by heat, acidic pH, endogenous mediators, and capsaicin (a component of hot chili peppers).
When intense, repetitive, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and their firing frequency increases for all stimulus intensities. This process, called sensitization, involves inflammatory mediators such as BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes. Sensitization occurs both at the peripheral nerve terminal (peripheral sensitization) and at the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization takes place in damaged or inflamed tissues, where inflammatory mediators trigger intracellular signal transduction in nociceptors, leading to increased production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes raise the excitability of nociceptor terminals and lower their activation threshold for mechanical, thermal, and chemical stimuli. Central sensitization happens when activity generated by nociceptors during inflammation heightens the excitability of nerve cells in the dorsal horn of the spinal cord. After injury and subsequent sensitization, stimuli that would normally be innocuous can trigger pain, a phenomenon known as allodynia. Sensitization is a significant process contributing to tenderness, soreness, and hyperalgesia (heightened pain intensity in response to the same noxious stimulus, such as a pinprick causing severe pain). An illustrative example of sensitization is sunburned skin, where gentle touch or a warm shower can produce severe pain.
Sensitization holds particular importance in deep tissues. Normally, viscera are relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera may cause significant discomfort when distended. However, when deep structures, such as joints or hollow viscera, are affected by a disease process with an inflammatory component, they typically become highly sensitive to mechanical stimulation.
In noninjured, noninflamed tissue, a substantial portion of Aδ and C fiber afferents innervating viscera are completely insensitive to known mechanical or thermal stimuli and remain inactive. Yet, in the presence of inflammatory mediators, these afferents become responsive to mechanical stimuli. Such afferents are termed silent nociceptors, and their distinct characteristics help explain how relatively insensitive deep structures can become sources of severe and debilitating pain and tenderness. Low pH, prostaglandins (PGs), leukotrienes, and other inflammatory mediators, such as BK, play a significant role in sensitization.
Primary afferent nociceptors do not merely convey information about tissue injury threats; they also play an active role in tissue protection by serving as neuroeffectors. Most nociceptors contain polypeptide mediators like substance P, calcitonin gene-related peptide (CGRP), and cholecystokinin. When activated, these mediators are released from the nociceptors' peripheral terminals. Substance P, for instance, is an 11-amino-acid peptide released in peripheral tissues by primary afferent nociceptors and possesses various biological functions. It acts as a potent vasodilator, triggers mast cell degranulation, attracts leukocytes, and enhances the production and release of inflammatory mediators. Interestingly, depleting substance P from joints has been shown to reduce the severity of experimental arthritis.

## Central Mechanism

Primary afferent nociceptors' axons enter the spinal cord through the dorsal root, terminating in the dorsal horn of the spinal gray matter. These primary afferent axon terminals make contact with spinal neurons responsible for transmitting pain signals to areas in the brain associated with pain perception. When primary afferents are stimulated by noxious stimuli, they release neurotransmitters from their terminals, exciting spinal cord neurons. The primary neurotransmitter released is glutamate, which rapidly stimulates the second-order dorsal horn neurons. Additionally, primary afferent nociceptor terminals release substance P and CGRP, which result in a slower and longer-lasting excitation of the dorsal horn neurons. Each primary afferent's axon connects with numerous spinal neurons, and each spinal neuron receives input from multiple primary afferents. The convergence of sensory inputs onto a single spinal pain-transmission neuron is significant because it gives rise to referred pain. All spinal neurons receiving input from viscera and deep musculoskeletal structures also receive input from the skin.
The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies afferent innervation to a structure. For instance, afferents supplying the central diaphragm originate from the third and fourth cervical dorsal root ganglia. These same ganglia's primary afferents supplying the skin of the shoulder and lower neck also come from there. As a result, sensory inputs from both the shoulder skin and the central diaphragm converge onto pain-transmission neurons in the third and fourth cervical spinal segments. Due to this convergence and the fact that spinal neurons are usually activated by skin inputs, the patient often mislocates the pain sensation produced by inputs from deep structures to a bodily area that roughly corresponds to the skin's innervated region from the same spinal segment. Consequently, inflammation near the central diaphragm is frequently reported as shoulder discomfort. This shift of pain sensation from the actual injury site is termed referred pain.
The majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons constitute the contralateral spinothalamic tract, which traverses the anterolateral white matter of the spinal cord, the lateral edge of the medulla, and the lateral pons and midbrain. The spinothalamic pathway is essential for pain perception in humans. Disruption of this pathway results in permanent deficits in pain and temperature discrimination.
Spinothalamic tract axons ascend to various thalamic regions. From these thalamic sites, the pain signal diverges significantly to several distinct regions of the cerebral cortex, each serving different aspects of the pain experience. One of these thalamic projections targets the somatosensory cortex, responsible for the sensory discriminative aspects of pain, such as its location, intensity, and quality. Other thalamic neurons project to cortical regions associated with emotional responses, like the cingulate and insular cortex. These pathways to the frontal cortex manage the affective or emotional dimension of pain, which leads to suffering and significantly influences behavior. The emotional dimension of pain induces fear as a constant companion of pain. Consequently, injuries or surgical lesions to frontal cortex areas activated by painful stimuli can reduce the emotional impact of pain while preserving the individual's ability to recognize noxious stimuli as painful.

## Pain Modulation

The intensity of pain resulting from injuries of similar magnitude can vary widely across different situations and individuals. For instance, athletes have been known to sustain severe fractures with minimal pain, and Beecher's well-known World War II survey revealed that many soldiers in combat did not seem bothered by injuries that would have caused excruciating pain in civilian patients. Moreover, the mere suggestion that a treatment will alleviate pain can have a significant analgesic effect, known as the placebo effect. Conversely, many patients find even minor injuries like venipuncture terrifying and unbearable, and the expectation of pain can induce pain even without an actual noxious stimulus. The suggestion that pain will worsen after receiving an inactive substance can also amplify its perceived intensity, known as the nocebo effect.
Expectation and other psychological factors have a substantial impact on pain intensity, and this can be explained by brain circuits that modulate pain-transmission pathway activity. One of these circuits has connections to the hypothalamus, midbrain, and medulla, selectively regulating spinal pain-transmission neurons via a descending pathway.
Functional brain imaging studies in humans have implicated this pain-modulating circuit in the pain relief induced by attention, suggestion, and opioid analgesic medications. Additionally, all component structures of this pathway contain opioid receptors and respond to direct application of opioid drugs. In animals, lesions of this descending modulatory system reduce the analgesic effect of systemically administered opioids like morphine. The most consistent way to activate this endogenous opioid-mediated modulatory system is through suggestions of pain relief or strong emotions unrelated to the painful injury, such as during intense threat or athletic competition. Following surgical procedures and administration of a placebo for pain relief, endogenous opioid-mediated pain relief is observed.
Pain-modulating circuits can either amplify or suppress pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and regulate spinal pain-transmission neurons. As a result, pain-transmission neurons can be activated by modulatory neurons, potentially generating a pain signal without a peripheral noxious stimulus. Human functional imaging studies have revealed increased activity in this circuit during migraine headaches, suggesting a central circuit that facilitates pain. This concept helps explain how psychological factors can contribute to chronic pain and how pain can be induced or intensified by suggestion or expectation.

## Neuropathic pain

Lesions in peripheral or central nociceptive pathways typically result in a loss or impairment of pain sensation. Paradoxically, damage or dysfunction in these pathways can also lead to pain. For instance, damage to peripheral nerves, as seen in diabetic neuropathy, or primary afferents, as in herpes zoster infection, can lead to pain referred to the body region innervated by the affected nerves. Pain can also arise from damage to the central nervous system (CNS), such as after trauma or vascular injury affecting spinal cord, brainstem, or thalamic regions containing central nociceptive pathways. These pains are termed neuropathic and are often severe and resistant to standard pain treatments.
Neuropathic pain typically features a distinct burning, tingling, or electric shock-like quality and may occur spontaneously without any apparent stimulus or be triggered by very light touch. These characteristics are uncommon in other types of pain. On examination, a sensory deficit usually coincides with the area of the patient's pain. Hyperpathia, an exaggerated pain response to non-painful or mild noxious stimuli, especially with repetitive application, is another characteristic of neuropathic pain; patients often complain that even the slightest touch elicits severe pain (referred to as allodynia). Notably, a topical 5% lidocaine patch has proven effective for postherpetic neuralgia patients who experience prominent allodynia.
Various mechanisms contribute to neuropathic pain. Similar to sensitized primary afferent nociceptors, damaged primary afferents, including nociceptors, become highly responsive to mechanical stimulation and may generate impulses even in the absence of stimulation. Increased sensitivity and spontaneous activity are, in part, due to an elevated density of sodium channels in the damaged nerve fibers. Additionally, damaged primary afferents may become sensitive to norepinephrine. Intriguingly, spinal cord pain-transmission neurons disconnected from their normal input may also exhibit spontaneous activity. Therefore, both central and peripheral nervous system hyperactivity contribute to neuropathic pain.
Patients who have sustained peripheral nerve injuries sometimes develop spontaneous pain within or beyond the region innervated by the affected nerve. This pain often presents as a burning sensation. Typically, this pain begins after a delay of hours to weeks and is accompanied by swelling of the affected extremity, periarticular bone loss, and arthritis in the distal joints. Early in the course of this condition, the pain may be alleviated by a local anesthetic block of the sympathetic innervation to the affected extremity. Damaged primary afferent nociceptors acquire sensitivity to adrenergic stimulation and can be triggered by sympathetic outflow. This constellation of spontaneous pain and signs of sympathetic dysfunction following injury is referred to as complex regional pain syndrome (CRPS). When it occurs following a recognizable nerve injury, it is known as CRPS type II (also called posttraumatic neuralgia or causalgia if severe). If a similar clinical presentation occurs without an obvious nerve injury, it is termed CRPS type I (also known as reflex sympathetic dystrophy). CRPS can result from various injuries, including bone fractures, soft tissue trauma, myocardial infarction, and stroke. Typically, CRPS type I resolves with symptomatic treatment, but in cases of persistent pain, detailed examination often reveals evidence of peripheral nerve injury. Although the pathophysiology of CRPS is not well understood, acute pain and signs of inflammation are often rapidly relieved by blocking the sympathetic nervous system. This suggests that sympathetic activity can activate undamaged nociceptors in the presence of inflammation. Patients with posttraumatic pain and inflammation and no other apparent explanation should be evaluated for signs of sympathetic hyperactivity.

## Treatment: Acute Pain

The primary goal in treating any pain is to identify and address the underlying cause. While immediate treatment can be initiated, efforts to diagnose and treat the root cause of the pain should always proceed alongside pain management. In some cases, treating the underlying condition may not provide immediate pain relief. Additionally, certain conditions are so painful that swift and effective pain relief is essential. Examples include the postoperative state, burns, trauma, cancer, or sickle cell crisis. In such cases, analgesic medications become the first line of treatment, and it's crucial for healthcare providers to be well-versed in their use.

### Aspirin, Acetaminophen, and Nonsteroidal Anti-Inflammatory Agents (NSAIDs)

These drugs are grouped together because they are used to manage similar types of pain and may share a similar mechanism of action. All these medications inhibit an enzyme called cyclooxygenase (COX), with the exception of acetaminophen, and most of them have anti-inflammatory properties, particularly at higher doses. They are especially effective for treating mild to moderate headaches and pain originating from musculoskeletal conditions.
COX inhibitors, including aspirin and NSAIDs, are the most commonly used analgesics because they effectively alleviate common types of pain and are available without a prescription. They are absorbed efficiently in the gastrointestinal tract and, with occasional use, generally have minimal side effects. However, chronic use of aspirin and NSAIDs can lead to gastric irritation, which is the most common side effect. Aspirin, in particular, is associated with the risk of gastric mucosal erosion, ulcers, bleeding, or perforation due to its irreversible effect on platelet COX, affecting blood clotting.
Older individuals and those with a history of gastrointestinal problems are at an increased risk when using aspirin and NSAIDs. Besides the well-known gastrointestinal risks, NSAIDs can also have a negative impact on kidney function in individuals prone to renal insufficiency, especially when there is a significant decrease in intravascular volume, as seen with chronic diuretic use or acute hypovolemia. Additionally, NSAIDs may raise blood pressure in some individuals, necessitating regular blood pressure monitoring for those on long-term treatment. Unlike aspirin and NSAIDs, acetaminophen rarely causes gastric irritation and does not affect platelet function.
Ketorolac and diclofenac, two parenteral (administered through injection) forms of NSAIDs, have extended the utility of this class of drugs in managing severe acute pain. These agents are potent and fast-acting, often replacing opioids as the primary treatment for many patients with severe headaches and musculoskeletal pain.
It's worth noting that there are two major types of cyclooxygenase: COX-1, which is constitutively expressed, and COX-2, which is induced during inflammation.

### Opioid Analgesics

Opioids are the most potent pain-relieving medications available. They have a broad spectrum of effectiveness and provide reliable and effective relief for severe pain. While opioids can cause side effects, most of these effects are reversible. Common opioid-related side effects include nausea, vomiting, itching, sedation, and constipation. Respiratory depression, although uncommon at standard analgesic doses, can be life-threatening and should be closely monitored. The opioid antagonist naloxone can rapidly reverse opioid-related side effects.
The fear of inducing addiction in patients is a concern for some healthcare providers and patients. However, the risk of patients becoming addicted to opioids when used for medical purposes is very low. For chronic pain, especially chronic noncancer pain, the risk of addiction in patients taking opioids on an ongoing basis remains small. The key principle in opioid use is to provide adequate pain relief, and healthcare providers should not hesitate to prescribe an adequate dose to ensure that patients are not suffering needlessly.
Patient-controlled analgesia (PCA) is a widely used approach for managing pain, especially postoperative pain. PCA devices allow patients to self-administer small, controlled doses of opioid medications. This approach is effective for achieving optimal pain relief and is often used in hospital settings. It can also be employed for short-term home care for patients with severe, uncontrolled pain.

### Other Routes of Administration

In addition to traditional oral and intravenous administration, opioids can be delivered through various routes to improve patient comfort and adherence. These include intranasal (e.g., butorphanol), rectal, transdermal (e.g., fentanyl and buprenorphine), and oral mucosal (e.g., fentanyl) routes. These alternative routes help avoid frequent injections in patients who cannot take oral medication and can provide steady plasma levels, improving patient comfort.
Newer agents like alvimopan and methylnaltrexone have been developed to address opioid-related side effects. These peripherally acting opioid antagonists can help reverse the adverse effects of opioids in the gastrointestinal tract and alleviate constipation.

### Combining Opioids with COX Inhibitors

When opioids are combined with COX inhibitors, their effects add up. This combination allows for the use of lower doses of each medication to achieve the same level of pain relief, reducing the severity of dose-related side effects. However, it's essential to be cautious when using fixed-ratio combinations of opioids with acetaminophen because of the risk of excessive acetaminophen exposure with escalating opioid doses. Excessive acetaminophen intake can lead to liver toxicity. Therefore, many practitioners avoid opioid-acetaminophen combination analgesics to mitigate this risk.

## Chronic Pain

Managing patients with chronic pain presents both intellectual and emotional challenges. The nervous system can become sensitized without an apparent cause, such as in cases of fibromyalgia or chronic headaches. In many instances, chronic pain evolves into a distinct condition on its own. Determining the exact cause of the pain is often difficult or even impossible, and such patients can be demanding and emotionally distressed. The traditional medical approach of searching for an underlying organic issue is often unhelpful. Conversely, psychological assessment and treatments based on behavior can be beneficial, especially in multidisciplinary pain management centers. Unfortunately, this approach is underutilized in current medical practice.
Various factors can contribute to, perpetuate, or worsen chronic pain. First, patients may have an inherently painful condition without a known cure, like arthritis, cancer, chronic daily headaches, fibromyalgia, or diabetic neuropathy. Second, secondary factors can continue to cause pain even after the initial disease has resolved, such as damaged sensory nerves, sympathetic nerve activity, and painful muscle spasms. Finally, psychological conditions can exacerbate or even cause pain.
Several aspects of a patient's medical history warrant special attention. Given that depression is the most common emotional issue in chronic pain patients, it's important to inquire about mood, appetite, sleep patterns, and daily activity. A standardized questionnaire like the Beck Depression Inventory can be a useful screening tool. It's crucial to recognize that major depression is a common but treatable and potentially life-threatening condition.
Other signs that a significant emotional issue may be contributing to a patient's chronic pain include pain occurring in unrelated areas, a history of recurrent but separate pain issues starting in childhood or adolescence, pain associated with emotional trauma, such as the loss of a loved one, a history of physical or sexual abuse, and current or past substance abuse.
During the physical examination, it's important to note whether the patient protects the painful area and avoids specific movements or postures due to pain. Identifying a mechanical aspect of the pain can be both diagnostic and therapeutic. Painful areas should be examined for deep tenderness, focusing on whether it's localized to muscle, ligaments, or joints. Chronic myofascial pain is common, and deep palpation may reveal localized trigger points, which are firm knots or bands in muscles. Pain relief following the injection of a local anesthetic into these trigger points supports the diagnosis. Evidence of nerve damage, such as sensory loss, heightened skin sensitivity (allodynia), weakness, muscle atrophy, or diminished deep tendon reflexes, suggests a neuropathic component to the pain. Symptoms indicative of sympathetic nervous system involvement include generalized swelling, changes in skin color and temperature, and hypersensitive skin and joint tenderness compared to the unaffected side. Pain relief following a sympathetic block supports this diagnosis, although its effectiveness can vary for chronic conditions, and the role of repeated sympathetic blocks remains unclear in the overall management of complex regional pain syndrome (CRPS).
An important principle when evaluating patients with chronic pain is to consider both emotional and somatic causes and perpetuating factors before initiating treatment. Addressing these aspects together, instead of postponing emotional evaluations until somatic causes are ruled out, can improve patient compliance by showing that the physician values their complaint's validity. Even when a somatic cause is identified, it's still prudent to explore other contributing factors. For instance, a cancer patient with painful bone metastases may also experience pain from nerve damage or depression. Optimal treatment necessitates assessing and managing each of these factors.

## Treatment: Chronic Pain

Once the evaluation is complete and the likely causes and factors that worsen the pain are identified, a specific and realistic treatment plan should be established. Part of this process involves identifying functional goals for therapy, such as achieving better sleep, resuming daily activities like shopping, or returning to work. A multidisciplinary approach, involving medications, counseling, physical therapy, nerve blocks, and possibly surgery, may be needed to improve the patient's quality of life. There are also minimally invasive procedures, like epidural injections of glucocorticoids for acute radicular pain or radiofrequency treatment of facet joints for chronic facet-related back and neck pain, which can be helpful for some patients with intractable pain. These interventions are guided by evolving criteria and are generally reserved for patients who have not responded to standard pharmacological treatments. Before invasive procedures, patients should typically be referred to a multidisciplinary pain clinic for a comprehensive evaluation. Such referrals aren't necessary for all chronic pain patients, as pharmacological management alone may suffice for some.

### Antidepressants

Tricyclic antidepressants (TCAs), particularly nortriptyline and desipramine, are useful in managing chronic pain. Despite being developed for depression treatment, TCAs have various biological activities at different doses, including analgesic effects in numerous chronic conditions. Their analgesic effect often occurs at lower doses and more rapidly than required for treating depression. Notably, even non-depressed chronic pain patients can experience pain relief from TCAs. TCAs have been shown to enhance the analgesic effect of opioids, making them valuable in severe persistent pain, such as that associated with cancer. However, TCAs have significant side effects, including orthostatic hypotension, drowsiness, cardiac conduction abnormalities, memory problems, constipation, and urinary retention, which can be particularly troublesome for elderly patients and additive to the side effects of opioid pain relievers. Selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, have milder side effects than TCAs but are less effective in pain relief. However, newer non-tricyclic antidepressants like venlafaxine and duloxetine, which inhibit both serotonin and norepinephrine reuptake, appear to maintain most of the pain-relieving effects of TCAs while having side effects more similar to SSRIs. These drugs may be preferable for patients unable to tolerate TCAs.

### Anticonvulsants and Antiarrhythmics

These medications are primarily useful for neuropathic pain. Drugs like phenytoin and carbamazepine were initially shown to relieve the pain of trigeminal neuralgia, characterized by brief, shooting, electric shock-like pain. More recently, newer anticonvulsants such as gabapentin and pregabalin have proven effective for a wide range of neuropathic pains, with favorable side effect profiles, often making them the first-line treatment choice.

### Cannabinoids

Cannabinoids are commonly used for their analgesic properties, though evidence suggests their effects on pain are usually modest, causing slight increases in pain threshold and variable reductions in clinical pain intensity. However, they tend to consistently reduce the unpleasantness of the pain experience and, in cancer-related pain, can alleviate the nausea and vomiting caused by chemotherapy. Cannabis and related compounds are further discussed in another chapter.

### Chronic Opioid Medication

Long-term opioid use is accepted for patients with pain resulting from malignant diseases. However, using opioids for chronic nonmalignant pain is controversial. Still, for many patients, opioids are the only option that provides meaningful pain relief. Opioids are potent and effective for a wide range of painful conditions but can lead to tolerance, physical dependence, and, in some cases, worsened pain (opioid-induced hyperalgesia) during long-term use. Thus, before starting opioid therapy, alternative options should be explored, and patients should be educated about the limitations and risks associated with opioids. Some opioid analgesics have mixed agonist-antagonist properties and can induce an abstinence syndrome when used concurrently with other opioids, creating practical challenges for patients on multiple opioid therapies. For long-term outpatient use of orally administered opioids, extended-release compounds such as methadone, levorphanol, extended-release morphine, oxycodone, or transdermal fentanyl can help maintain stable analgesic blood levels, potentially minimizing side effects. Extended-release opioids are generally approved for patients already using other opioids and should not be the first choice for pain management. While long-acting opioids may provide superior pain relief for patients with constant pain, those with intermittent severe episodic pain might benefit more from periodic use of short-acting opioids. Opioid use frequently leads to constipation, which should be managed. Peripherally acting opioid antagonists that reverse opioid-induced constipation without affecting pain relief are a recent development and are beneficial for patients. It's important to mention that the introduction of extended-release oxycodone (OxyContin) led to a significant increase in emergency room visits and deaths, primarily due to nonmedical use of prescription opioids. These issues led to increased scrutiny of opioid prescribing practices and the development of guidelines and monitoring programs to address prescription drug abuse and reduce the improper prescription of opioids.

### Treatment of Neuropathic Pain

Treatment for neuropathic pain should be individualized. Two key principles should guide therapy: providing quick relief and minimizing side effects. For example, patients with postherpetic neuralgia and heightened cutaneous sensitivity can benefit from topical lidocaine (Lidoderm patches) for immediate relief without significant side effects. Anticonvulsants like gabapentin or pregabalin, as well as antidepressants such as nortriptyline, desipramine, duloxetine, or venlafaxine, are first-line treatments for neuropathic pain. Systemic administration of antiarrhythmic drugs like lidocaine and mexiletine is less effective. While intravenous lidocaine infusion can provide temporary pain relief for various neuropathic pain types, it's often short-lived. Mexiletine, an oral lidocaine derivative, is associated with frequent gastrointestinal side effects and is poorly tolerated. The choice of the initial drug class isn't standardized, but due to the relatively high doses of anticonvulsants required for pain relief, sedation can be problematic. Sedation is less common with TCAs but more so with serotonin/norepinephrine reuptake inhibitors (SNRIs) like venlafaxine and duloxetine. Therefore, SNRIs are recommended as the first-line option for elderly patients or those requiring high-level mental activity. In contrast, opioids should be considered second- or third-line treatments. Opioids, while highly effective for many types of pain, can cause sedation, and their effectiveness may decrease over time, leading to dose escalation and occasional worsening of pain. Tramadol and tapentadol, two drugs with mixed opioid and norepinephrine reuptake inhibition actions, offer alternatives to pure opioids. Tramadol is relatively weak, sometimes effective when other non-opioid analgesics fail. Tapentadol is a stronger opioid, but its analgesic action is potentially enhanced by norepinephrine reuptake inhibition. Combining medications from different classes can optimize pain control. Repeated botulinum toxin injections are a promising approach for treating focal neuropathic pain, especially post-herpetic, trigeminal, and post-traumatic neuralgias.
It's essential to understand that many patients with chronic pain seek medical care primarily for relief because physicians can provide the necessary medications. One of a physician's main responsibilities is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medications is a crucial step in achieving this goal.