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Pain Medication

Pain Medication

Analgesics are medications that are used to manage and treat pain. There are several types of medications in this category (acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, local anesthetics, and opioids). This activity examines the indications, actions, and contraindications for all of the drug classes previously mentioned as useful agents in treating pain and other specific disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors relevant for interprofessional healthcare team members in managing patients with acute and chronic pain and related conditions (e.g., off-label uses, dosing, and monitoring).

Explain the need for naloxone administration.
Describe the most common physical exam findings associated with NSAID toxicity.
Determine the most common side effects of acetaminophen therapy.
Examine the significance of improving interprofessional care coordination in pain control medication selection for patients with acute and chronic pain.
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According to the International Association for the Study of Pain (IASP), pain is an unpleasant experience (sensory and emotional) related to a potential or confirmed tissue damage or described in such terms.[1] Nonetheless, the classification for pain management medications is stable; categories are nonopioid and opioid analgesic agents.

Analgesics that are not opioids

Acetaminophen (paracetamol): mild to moderate pain, moderate to severe pain (as an adjunct to opioid therapy), and temporary fever reduction. Acetaminophen should not be used to treat neuropathic pain because there is no evidence that it works[5][6][7].
Nonsteroidal anti-inflammatory drugs (NSAIDs): These medications treat mild-to-moderate pain and pain associated with inflammation and temporarily reduce fever. Like the previous medication, NSAIDs have no evidence for treating neuropathic pain. Some NSAIDs have non-pain indications (for example, aspirin for secondary prevention of myocardial infarction), which this review will not cover.
Selective serotonin and norepinephrine reuptake inhibitors (SNRIs), particularly duloxetine, tricyclic antidepressants (TCAs), particularly amitriptyline, have shown efficacy in several neuropathic pain conditions. As a result, they are recommended as the first line of treatment.[9] Furthermore, in addition to their respective indications for psychiatric disorders like major depressive disorder and generalized anxiety disorder, these medications are also indicated for pathologies like fibromyalgia and chronic musculoskeletal pain. Antidepressants are also recommended as a preventative treatment for migraine and tension headaches (amitriptyline). Both pharmacological groups appear to be more effective in patients who have depressive symptoms as well as pain as a comorbidity than in patients who only have pain.[7][9]
Antiepileptic medications: Several antiepileptic drugs have analgesic properties due to their mechanism of action of lowering neurotransmitter release or neuronal firing. Gabapentin and pregabalin are the most commonly used antiepileptics for pain relief.[7]
Gabapentin is used to treat postherpetic neuralgia and neuropathic pain in adults.
Pregabalin is used to treat neuropathic pain caused by diabetic peripheral neuropathy or spinal cord injury and postherpetic neuralgia and fibromyalgia.
Trigeminal or glossopharyngeal neuralgia can be treated with oxcarbazepine and carbamazepine.
Lidocaine is one of the most commonly used medications in this drug class, which is FDA-approved for postherpetic neuralgia and recommended for peripheral neuropathic pain.
Opioid Substitutes

Opioids are a class of medications that have structural similarities to the natural plant alkaloids found in opium, which was originally derived from the resin of the opium poppy, Papaver somniferum.[11] They are widely recognized as the most effective and widely used drugs in treating severe pain.

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Action Mechanism
Analgesics that are not opioids

Acetaminophen (paracetamol): This drug’s precise mechanism of action is still unknown. Although some consider acetaminophen a nonsteroidal anti-inflammatory drug (NSAID), it lacks anti-inflammatory properties. It does not bind to the active site of either cyclooxygenase (COX) enzyme (COX-1 or COX-2). However, there is a theory that acetaminophen inhibits a different variant of COX-1, also known as COX-3, but human studies have yet to confirm this. Nonetheless, decreased COX pathway activity leads to decreased prostaglandin synthesis in the central nervous system, resulting in analgesia (serotonergic inhibitory pathways) and antipyresis (hypothalamic heat-regulating center).
NSAIDs: The primary action mechanism is the cyclooxygenase enzyme’s inhibition, which inhibits prostaglandin synthesis. These drugs are classified according to their chemical structure and selectivity: acetylated salicylates (aspirin), non-acetylated salicylates (diflunisal), propionic acids (ibuprofen, naproxen), acetic acids (indomethacin, diclofenac), anthranilic acids (meclofenamate, mefenamic acid), enolic acids (Meloxicam (celecoxib, etoricoxib). Most NSAIDs have little selectivity in inhibiting both COX isoforms (COX-1 and COX-2). Those that bind with higher affinity to one or both (for example, aspirin and coxibs) will exert varying degrees of anti-inflammatory, analgesic, and antipyretic effects. As a result, low doses of aspirin have an antiplatelet effect, whereas high doses have an analgesic effect.
Tricyclic antidepressants (TCAs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of two important neurotransmitters: serotonin and noradrenaline. This inhibition increases the central nervous system’s descending inhibitory pathways related to pain. TCAs also act on cholinergic, histamine, beta2 adrenergic, opioid, and N-methyl-D-aspartate (NMDA) receptors and sodium channels.
Antiepileptic medications: Gabapentin and pregabalin are both ligands for the voltage-dependent calcium channel subunit, which is overexpressed in patients with neuropathic pain. These drugs reduce neuronal excitability by inhibiting the calcium-dependent release of excitatory neurotransmitters.
Like other local anesthetics, Lidocaine stabilizes the neuronal membrane by blocking sodium ion channels on the internal surface of nerve cell membranes. As a result, pain conduction via nerve impulses is impaired at the site of action, contributing to the absence of systemic effects.[24]
Opioid antagonists

Most clinically relevant opioids act primarily on “mu receptors” and are thus classified as “mu agonists.”[25] However, opioids may also act on receptors such as kappa, delta, and sigma (all of them, including me, are G protein-coupled receptors). Different physiological effects occur depending on which receptor is activated (i.e., spinal and supraspinal analgesia). Opioids influence both presynaptic and postsynaptic neurons. Opioids inhibit the release of neurotransmitters such as substance P and glutamate by blocking calcium channels on nociceptive afferent nerves. Opioids increase the activity of potassium channels postsynaptically, hyperpolarizing cell membranes and increasing the required action potential to generate nociceptive neurotransmission[12][17].

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Analgesics that are not opioids

Adults should take 650 to 1000 mg every 4 to 6 hours, with a maximum daily dose of 4 grams of acetaminophen (paracetamol). In children, the recommended dose is 15 mg/kg every 6 hours, with a maximum daily dose of 60 mg/kg.[26] Acetaminophen can be taken orally (tablet, capsule, syrup, oral solution, or suspension), rectally (rectal suppository), or intravenously.[6]
Nonsteroidal anti-inflammatory drugs (NSAIDs): There are currently over 20 different NSAIDs on the market. Several factors influence the agent’s selection (e.g., comorbidities and risk of bleeding). Furthermore, the response to different NSAIDs varies between patients, and the mechanisms underlying these disparities are only partially understood. As a result, doses vary depending on the drug, and the recommendation is to prescribe the lowest effective dose for each patient for the shortest time possible. The followings are some commonly used NSAIDs and their doses for analgesia and anti-inflammation:
Aspirin (acetylsalicylic acid) is taken in doses ranging from 325 to 650 mg every 4 to 6 hours. The maximum daily dose is 4000 mg. Aspirin can be taken orally (caplet, capsule, tablet) or really (suppository).
50 mg diclofenac every 8 hours. The maximum daily dose is 150 mg. Diclofenac can be taken orally (tablet, capsule, packet), intravenously, topically (cream, gel, patch, solution), or ophthalmically.
Ibuprofen is taken in 400 mg increments every 4 to 6 hours. The maximum daily dose is 3200 mg (acute) or 2400 mg (chronic) (chronic). Ibuprofen can be taken orally (via capsule, tablet, or suspension) or intravenously.
Indomethacin: 25 to 50 mg every 8 to 12 hours for immediate release. 75 mg once or twice daily, controlled release. The maximum daily dose is 150 mg. Indomethacin can be taken orally (via capsule or suspension), intravenously, or really (via suppository).
Meloxicam: The recommended dose is 7.5 to 15 mg once daily. The maximum dose is 15 mg. Meloxicam can be taken orally (as a tablet, capsule, or suspension) or intravenously.
Naproxen: 250 to 500 mg every 12 hours (base) or 275 to 550 mg every 12 hours (high dose) (naproxen sodium). The maximum daily dose for naproxen base is 1250 mg acute or 1000 mg chronic, and for naproxen sodium, it is 1375 mg acute or 1100 mg chronic. Naproxen is only available orally (via capsule, suspension, or tablet).
Celecoxib: 200 mg once a day or 100 mg every 12 hours. The maximum daily dose is 400 mg. Celecoxib is only available as an oral (capsule) medication.
Antidepressant medications: Amitriptyline and duloxetine have the best-documented analgesic effects among tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors, respectively.
Amitriptyline is taken orally (as a tablet) once daily or in two divided doses of 25 to 150 mg. The daily and single maximum doses are 75 mg and 150 mg, respectively. Patients 65 years and older should exercise caution when receiving more than 75 mg daily doses.
Duloxetine is taken orally (via capsule) once daily or in two divided doses of 60 to 120 mg. The maximum daily dose is 120 mg. [7][28]
Medication for epilepsy:
Gabapentin: 300 to 600 mg orally three times per day (capsules, tablets, solution) with a maximum daily dose of 1800 mg for postherpetic neuralgia or 300 to 1200 mg orally three times per day with a maximum daily dose of 3600 mg.
Pregabalin: 300 to 600 mg/day, divided into two doses.[7]
Anesthetics used locally:
Lidocaine is available as a patch in concentrations of 1.8% or 5%. Applying 1-3 patches to intact skin for up to 12 hours per day is recommended. Topical solutions, creams, gels, ointment, and lotions are also commercially available.[7]
Opioid antagonists
Pain Medication
The following routes of administration are available for opioids: oral, transdermal, intramuscular, intravenous, subcutaneous infusion, rectal, epidural, intrathecal, intranasal, and transmucosal.[17][30] The rationale for each route of administration, dosage range, and dosage form depends on several factors. Please see the American Pain Society guidelines for more information.

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Negative Effects
Analgesics that are not opioids

Acetaminophen (paracetamol): This medication is safe and effective when used correctly. The adverse effects that have been documented vary depending on the route of administration. Acetaminophen may cause any of the following side effects when taken orally or rectally:
Reactions such as rashes or hypersensitivity (toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome)
Anemia, leukopenia, neutropenia, and pancytopenia are all hematological conditions.
Disorders of metabolism and electrolytes
Serum bicarbonate levels have dropped.
Alkaline phosphatase elevation [5][6][27]
Adverse effects of intravenous administration include nausea, vomiting, pruritus, constipation, and abdominal pain.[6] The most common adverse reactions in pediatric patients, regardless of the route of administration, are nausea, vomiting, agitation, constipation, pruritus, and atelectasis.

Nonsteroidal anti-inflammatory medications (NSAIDs)
Nausea, anorexia, dyspepsia, abdominal pain, ulcers, gastrointestinal bleeding, perforation, constipation, and diarrhea are all symptoms of gastrointestinal problems.
Cardiovascular: Hypertension, decreased antihypertensive medication effectiveness, myocardial infarction, stroke, and thromboembolic events (last three with selective COX-2 inhibitors); inhibit platelet activation, bruising, and bleeding.
Renal: Retention of salt and water, deterioration of kidney function, edema, decreased effectiveness of diuretic medications, decreased urate excretion, hyperkalemia, analgesic nephropathy
Headache, dizziness, vertigo, confusion, depression, seizure threshold reduction, and hyperventilation are all symptoms of the central nervous system (salicylates)
Vasomotor rhinitis, asthma, urticaria, flushing, hypotension, and shock are all symptoms of hypersensitivity.
Toxicity to the liver [8][7][21]
Please see the StatPearls article for the specific NSAID for a complete list of adverse effects.

Medications for depression
Amitriptyline can cause altered mental status, arrhythmias, constipation, decreased libido, dizziness, drowsiness, dry mouth, headache, hyperhidrosis, an increased risk of suicidal thoughts, micturition disorders (i.e., urinary retention), nausea, orthostatic hypotension, tremor, and weight gain.
Nausea, headache, dry mouth, drowsiness, dizziness, abdominal pain, constipation, increased blood pressure, and increased risk of suicidal thoughts.
Medication for epilepsy
Gabapentin side effects include dizziness, drowsiness, ataxia, peripheral edema, and confusion. Anaphylaxis, suicidality, depression, fever, infection, Steven-Johnson syndrome, angioedema, erythema multiforme, and rhabdomyolysis are among the more serious side effects.
Pregabalin side effects include dizziness, sleepiness, headache, peripheral edema, nausea, weight gain, disorientation, blurred vision, and an increased risk of suicidal ideation.[7]
Anesthetics used locally
Lidocaine causes pain at the application site, pruritus, erythema, and skin irritation.[7]
Opioid antagonists

Opioids cause a wide range of systemic adverse effects, including:

Vomiting and nausea
Cough management
Histamine secretion (urticaria, pruritus, hypotension, tachycardia)
Suppression of the endocrine system
Cardiovascular problems (i.e., bradycardia)
Depression of the respiratory system
The rigidity of skeletal muscles
Tolerance (chronic application) (chronic application)
Physical reliance (chronic application)
Chronic opioid-induced hyperalgesia and allodynia [17][12]
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Analgesics that are not opioids

Hypersensitivity to acetaminophen or its excipients, severe hepatic impairment, or severe active hepatic disease. Experts are currently debating whether hepatic impairment should be considered a contraindication because it would result in lower levels of the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).[6][32] It is important to note that pregnancy is not a contraindication for acetaminophen administration.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Hypersensitivity is the only major contraindication to NSAID use. However, the following conditions necessitate avoidance, temporary suspension, or extremely cautious use:
>50 years old, with a family history of gastrointestinal (GI) disease/bleeding.
NSAID-related GI problems in the past (e.g., gastritis)
The stomach ulcer
Personal GI bleeding history
Uncontrolled hypertension
Renal dysfunction
IBS is an abbreviation for Irritable Bowel Syndrome.
IBD (Irritable Bowel Disease)
Coronary artery bypass grafting
Bypass surgery for the stomach
Pregnancy (third trimester) (third trimester)
Stroke (excluding aspirin) (excluding aspirin)
Acute ischemic attack (excluding aspirin)
Acute myocardial infarction (excluding aspirin)
[7][21] Congestive heart failure (excluding aspirin)
Medication for depression:
Amitriptyline: Hypersensitivity, use with or within 14 days of MAOIs, use with cisapride, recent myocardial infarction, arrhythmias, acute heart failure, severe liver impairment.
Hypersensitivity, liver impairment, severe renal failure (e.g., CrCl 30 mL/minute), end-stage renal disease (ESRD), coadministration with or within 14 days of MAOIs, concurrent use of linezolid, thioridazine, methylene blue, or potent CYP1A2 inhibitors, uncontrolled narrow-angle glaucoma. Patients with hypertension or cardiac disease should exercise caution.[7][9][22]
Antiepileptic drugs: The only known contraindication to gabapentin and pregabalin is hypersensitivity to the drug or its excipients. On the other hand, patients with impaired renal function require dose adjustment.[7]
Local anesthetics: Lidocaine is contraindicated in patients with a history of sensitivity to any amide-type local anesthetic or its excipients. Furthermore, lidocaine patches should only be applied to intact skin.[24]
Opioid antagonists

Severe respiratory insufficiency
Suicidal ideation or acute mental instability
QTc interval greater than 500 milliseconds (methadone)
Substance abuse in the family and personal history
Tolerance, serious adverse effects, or lack of efficacy to other opioids with structurally similar structures
Impairment of the renal or hepatic systems (depending on the specific drug metabolism and excretion)[17].
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Analgesics that are not opioids

Acetaminophen (paracetamol) is a medication that is considered safe when used properly. Because toxicity occurs at doses greater than 150 mg/kg, the therapeutic index is estimated to be around 10. .[33]
Nonsteroidal anti-inflammatory drugs (NSAIDs): In healthy patients, there is no need for routine monitoring of NSAID acute administration. Patients who use NSAIDs regularly (e.g., rheumatoid arthritis) and those considered at high risk for NSAID toxicity (e.g., liver or renal disease) should have a minimum of CBC, renal, and hepatic function tests. Depending on clinical suspicion and findings, additional tests may be ordered.[8]
Medications for depression
Allow 6 to 8 weeks for an adequate trial of amitriptyline. Consider switching to another TCA, such as imipramine or nortriptyline, if patients achieve adequate pain relief but cannot tolerate the adverse reactions. Consider switching the dose to bedtime if the patient has concurrent insomnia or daytime sleepiness. Patients should be checked regularly for the following parameters: heart rate, blood pressure, ECG (for older adults or those with preexisting cardiac disease), blood glucose, weight and BMI, and an electrolyte panel (high-risk population). Patients should also be evaluated for suicidal ideation and mood lability.
Allow 6 to 8 weeks for an adequate trial of duloxetine. Patients should be checked regularly for blood pressure (especially in hypertensive patients), liver and renal function tests (as clinically indicated), blood glucose and HbA in diabetics, and serum sodium in high-risk populations. In addition, clinicians should screen patients for suicidal ideation[7][9][28].
Antiepileptic medications: Before and during treatment, healthcare providers should assess baseline creatinine levels in patients taking gabapentin or pregabalin. Patients should also be followed up for regular screenings for depression, behavioral changes, and suicidality.
Local anesthetics: Because Lidocaine has a narrow therapeutic index, patients with severe hepatic impairment, patients receiving prolonged infusions, or patients with broken or inflamed skin should be monitored for elevated plasma levels. There have also been documented cases of methemoglobinemia associated with the use of local anesthetics, though they are extremely rare when it comes to patch administration. Methemoglobinemia symptoms include cyanotic skin discoloration and abnormal blood coloration.[24]
Opioid Substitutes

Clinicians should conduct regular evaluations of their patients. The level of pain control and the physical examination should be the focus of follow-ups (vital signs, signs of misuse, abuse, or addiction; respiratory and mental status; signs or symptoms of hypogonadism or hypoadrenalism).

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