Analgesics are medications used in the management and treatment of pain. They include several classes of medications (acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, local anesthetics, and opioids).

Indications

According to the International Association for the Study of Pain (IASP), pain is defined as an unpleasant experience (sensory and/or emotional) related to a potential or confirmed tissue damage or described in such terms. Currently, the debate is ongoing whether or not this definition should be modified. Nonetheless, the classification for pain management medications is stable; categories are nonopioid analgesic agents and opioid analgesic agents.

Nonopioid analgesic agents

• Acetaminophen (paracetamol): Mild to moderate pain, moderate to severe pain (as adjunctive therapy to opioids), and temporary reduction of fever. Acetaminophen should not be used for neuropathic pain since there is no documented effect.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): These drugs are used for mild-to-moderate pain, pain associated with inflammation, and temporary reduction of fever. Similar to the previous medication, NSAIDs have no evidence for the management of neuropathic pain. Some NSAIDs have other non-pain-related indications (eg., aspirin use for secondary prevention of myocardial infarction), which will not be covered in this review.
• Antidepressant medications: Selective serotonin and norepinephrine reuptake inhibitors (SNRIs), particularly duloxetine,  and tricyclic antidepressants (TCAs), especially amitriptyline, have demonstrated efficacy in a variety of neuropathic pain conditions. Thus they are recommended as the first line of treatment. Furthermore, besides their respective indications for psychiatric disorders such as major depressive disorder and generalized anxiety disorder, these medications are indicated for other pathologies such as fibromyalgia and chronic musculoskeletal pain. Also, antidepressants are recommended as a prophylactic treatment for migraine and tension-type headaches (amitriptyline). Both of the pharmacological groups seem to be more effective in patients with depressive symptoms and pain as comorbidity than in those patients with pain alone.
• Antiepileptic medications: Several antiepileptic drugs are also known for their analgesic properties through their mechanism of action of lowering neurotransmitter release or neuronal firing. The most common antiepileptics used for pain treatment are gabapentin and pregabalin.
  • Gabapentin: Postherpetic neuralgia in adults and neuropathic pain.
  • Pregabalin: Neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, postherpetic neuralgia, and fibromyalgia.
  • Oxcarbazepine and carbamazepine: trigeminal or glossopharyngeal neuralgia
• Local anesthetics: Lidocaine is among the most commonly used medications in this drug class, which is FDA approved for postherpetic neuralgia and recommended for peripheral neuropathic pain.

Opioid Agents

Opioids are a broad class of medications with structural resemblance to the natural plant alkaloids found in opium, which was originally derived from the resin of the opium poppy, Papaver somniferum. They are recognized as the most effective and widely used drugs in treating severe pain.  Opioids have been among the most controversial analgesics, particularly because of their potential for addiction, tolerance, and side effects.  Although opioids have indications for acute and chronic pain treatment, the Center for Disease Control and Prevention’s guidelines recommends that only if the expected benefits for both pain and function outweigh the risks, clinicians should prescribe opioids at the lowest effective dose and for the shortest expected duration to treat the pain severe enough to require opioids.

Opioids are available in diverse dosage forms to use for several routes of administration: oral, transdermal, intramuscular, intravenous, subcutaneous infusion, rectal, epidural, intrathecal, intranasal, and transmucosal.  The rationale for each route of administration, dosage range, and dosage form is dependent on a number of factors. For more detailed information, please review the American Pain Society guidelines. 

Opioids produce a variety of different systemic adverse effects, including:

• Dysphoria/euphoria
• Sedation,
• Constipation
• Nausea and vomiting
• Cough suppression
• Miosis
• Histamine release (urticaria, pruritus, hypotension, tachycardia)
• Endocrine systems suppression
• Cardiovascular disorders (i.e., bradycardia)
• Respiratory depression
• Skeletal muscle rigidity
• Tolerance (chronic application)
• Physical dependence (chronic application)
• Opioid-induced hyperalgesia and/or allodynia (chronic application)

Nonopioid analgesic agents

• Acetaminophen (paracetamol): The precise mechanism of action for this drug remains unclear to date. Although it is considered for some as a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen lacks anti-inflammatory properties.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): The primary mechanism of action is the inhibition of the cyclooxygenase enzyme, thereby inhibiting prostaglandin synthesis. Drugs in this group are categorized according to 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, piroxicam), naphthylalanine (nabumetone), and selective COX-2 inhibitors (celecoxib, etoricoxib).
• Antidepressant medications: Both 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 descending inhibitory pathways of the central nervous system related to pain.
• Antiepileptic medications: Both gabapentin and pregabalin act on voltage-dependent calcium channels, which overexpress in patients with neuropathic pain. By reducing this calcium-dependent release of excitatory neurotransmitters, these drugs decrease neuronal excitability.
• Local anesthetics: As with other local anesthetics, lidocaine stabilizes the neuronal membrane by inhibiting sodium ion channels on the internal surface of nerve cell membranes. Thus, pain conduction through nerve impulses becomes impaired at the site of action, which contributes to the absence of systemic effects.

Adverse Effects

Nonopioid analgesic agents

• Acetaminophen (paracetamol): This drug is a safe and effective medication when used correctly. Documented adverse effects depend on the route of administration. If administered orally or rectally, acetaminophen may cause any of the following:
  • Rash or hypersensitivity reactions
  • Hematological: anemia, leukopenia, neutropenia, pancytopenia
  • Nephrotoxicity
  • Metabolic and electrolyte disorders
    • Decreased serum bicarbonate
    • Hyponatremia
    • Hypocalcemia
    • Hyperammonemia
    • Hyperchloremia
    • Hyperuricemia
    • Hyperglycemia
    • Hyperbilirubinemia
    • Elevated alkaline phosphatase 

If administered intravenously, adverse effects include nausea, vomiting, pruritus, constipation, and abdominal pain.  For pediatric patients, regardless of the route of administration, the most common adverse reactions are nausea, vomiting, agitation, constipation, pruritus, and atelectasis.

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Gastrointestinal: Nausea, anorexia, dyspepsia, abdominal pain, ulcers, gastrointestinal hemorrhage, perforation, constipation, diarrhea
  • Cardiovascular: Hypertension, decreased effectiveness of anti-hypertensive medications, myocardial infarction, stroke, and thromboembolic events (last three with selective COX-2 inhibitors); inhibit platelet activation, propensity for bruising, and hemorrhage.
  • Renal: Salt and water retention, deterioration of kidney function, edema, decreased effectiveness of diuretic medications, decreased urate excretion, hyperkalemia, analgesic nephropathy
  • Central nervous system: Headache, dizziness, vertigo, confusion, depression, lowering of seizure threshold, hyperventilation (salicylates)
  • Hypersensitivity: Vasomotor rhinitis, asthma, urticaria, flushing, hypotension, shock.
  • Hepatotoxicity

Antidepressant medications

Amitriptyline: Altered mental status, arrhythmias, constipation, decreased libido, dizziness, drowsiness, dry mouth, headache, hyperhidrosis, increased risk of suicidal thoughts, micturition disorders (i.e., urinary retention), nausea, orthostatic hypotension, tremor, weight gain.

Duloxetine: Nausea, headache, dry mouth, somnolence, dizziness, abdominal pain, constipation increased blood pressure, increased risk of suicidal thoughts.

Antiepileptic medications

Gabapentin: The most common side effects are dizziness, somnolence, ataxia, peripheral edema, and confusion. Among other, more serious adverse effects are anaphylaxis, suicidality, depression, fever, infection, steven-Johnson syndrome, angioedema, erythema multiforme, and rhabdomyolysis.

Pregabalin: Dizziness, somnolence, headache, peripheral edema, nausea, weight gain, disorientation, blurred vision, increased risk of suicidal thoughts.

Local anesthetics

Lidocaine: Application-site pain, pruritus, erythema, and skin irritation.