Pharmacologic Management of Pain

Pharmacologic Management of Pain

Trinh Pham

Pharmacologic Management of Pain

Pain can arise from a broad variety of causes and can be categorized according to duration (acute vs. chronic) or the underlying mechanisms causing the pain (nociceptive vs. neuropathic vs. inflammatory). Healthcare providers should be knowledgeable about the analgesic options that are available and the types of pain that may be responsive to those analgesics. There are three broad categories of analgesic medications—nonopioid analgesics, opioid analgesics, and adjuvant analgesics—that can be used to manage pain symptoms. A multimodal approach to pain management using a combination of these different categories of analgesics with different mechanisms of action may improve pain control via additive or synergistic effects of each of these categories of drugs in addition to reducing the risk of adverse effects because lower doses of each drug will be utilized. A sound understanding of the pharmacology of analgesic medications and their appropriate use facilitates effective prescribing, administration, and dispensing of the analgesics used to manage a patient’s pain diagnosis. This chapter reviews the pharmacologic approach to the management of pain, the goal of which is to maximize efficacy of analgesic drug therapy while minimizing adverse effects and toxicities.

Nonopioid Analgesics

Nonopioid analgesics include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs possess analgesic, anti-inflammatory, and anti-pyretic effects. Unlike NSAIDs, acetaminophen has no anti-inflammatory activity. These nonopioid analgesics are effective for the management of mild to moderate pain, and NSAIDs are effective for pain that has an inflammatory component.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective anti-inflammatory, antipyretic, and analgesic agents that are commonly used in the treatment of acute and chronic pain, rheumatoid arthritis, and osteoarthritis. They exert their pharmacologic effects via inhibition of one or both isoforms of the cyclooxygenase (COX) enzymes (COX-1 and COX-2), which catalyze the conversion of arachidonic acid to prostaglandins (PGs) and thromboxanes (Theken, 2018). Drugs that inhibit both COX-1 and COX-2 are known as nonselective NSAIDs (nsNSAIDs) and drugs that inhibit only COX-2 are referred to as selective NSAIDs. Inhibition of COX-1 is thought to be principally responsible for the adverse effects following prolonged administration of nonselective COX inhibitors, whereas selective COX-2 inhibition accounts for the anti-inflammatory, antipyretic, and analgesic efficacy of NSAIDs (Huntjens, Danhof, & Della Pasqua, 2005). COX-1 is constitutively expressed in most tissue types, and the PGs produced by this isoform mediate functions such as cytoprotection of the gastric mucosa, regulation of renal blood flow, and platelet aggregation. As a consequence, nsNSAIDs that inhibit not only COX-2 but also COX-1 lead to a greater risk of adverse effects such as gastrointestinal (GI) ulceration, bleeding, and nephrotoxicity. COX-2 is an inducible enzyme and its expression is highly restricted under basal conditions; however, its expression is greatly increased at inflammatory sites in response to cytokines such as interferon γ, tumor necrosis factor α, and interleukin 1 (Bacchi, Palumbo, Sponta, & Coppolino, 2012). PGE2 and PGI2 mediate central and peripheral nociceptive responses. Additionally, the decrease in the synthesis of PGE2 and PGI2, which are also considered to be vasodilating PGs, produces anti-inflammatory action and indirect reduction of edema. Thus, NSAIDs exert their analgesic effects by inhibiting PGs that promote peripheral and central sensitization (Bacchi et al., 2012), and they are effective in treating pain that occurs as a consequence of COX pathway activation, such as with acute injuries or arthritis (Theken, 2018).

All NSAIDs inhibit COX enzymes; however, there is marked diversity within the class with regard to their chemical properties, pharmacokinetics, and degree of selectivity for COX-2 over COX-1. NSAIDs may be classified on the basis of their in vitro COX enzyme selectivity (Table 7-1) (Bacchi et al., 2012; Warner et al., 1999) or their chemical structure (Table 7-2) (Antman et al., 2007; Wickham, 2017). Although COX selectivity characteristics of individual NSAIDs have been determined in vitro, it is difficult to translate the clinical risk of adverse effects for specific patients based on COX-2 selectivity. The differences in the NSAID characteristics may contribute to the variability in analgesic efficacy, adverse effect profile, and patient pReferences for specific NSAIDs. Studies comparing the efficacy of individual NSAIDs have not identified greater efficacy of any individual NSAID over another; therefore, the analgesic efficacy of distinct NSAIDs is considered to be similar and no one drug is considered to be more effective than others within the class (Theken, 2018). The choice of a particular NSAID depends on the specific pharmacokinetic properties, adverse effect profile, availability, and cost of the individual agents. NSAIDs that are designed with enhanced dissolution and rapid absorption properties facilitate a shorter time to analgesic effect, which is a desirable characteristic for treating acute pain. NSAIDs with extended half-lives achieve stable drug concentrations with less frequent dosing
and are preferred for treating chronic, persistent pain, with an understanding that the risk of adverse effects is increased because of the long half-life. NSAIDs have an analgesic ceiling dose, above which only toxicity occurs with no additional pain relief. Because there is high interpatient variability in response to individual NSAIDs, it is clinically reasonable to switch to another drug member of the NSAID class if there is inadequate response after a minimum of 1 month therapy of a particular NSAID (Simon & Strand, 1997).

Table 7-1. Classification of NSAIDs Based on Their In Vitro COX-2 Inhibition Activity




Group 1

(<5-fold COX-2 selectivity)

Poorly selective NSAIDs that fully inhibit both COX-1 and COX-2

Aspirin, diclofenac, diflunisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, piroxicam, sulindac, tolmetin

Group 2

(5- to 50-fold COX-2 selectivity)

NSAIDs capable of inhibiting both COX-1 and COX-2 with preferential selectivity toward COX-2

Celecoxib, etodolac, meloxicam

Group 3

(>50-fold COX-2 selectivity)

NSAIDs that strongly inhibit COX-2 but only weakly inhibit COX-1

Rofecoxib (no longer on the market in the United States)

Group 4

NSAIDs that seem to be only weak inhibitors of both COX-1 and COX-2

Sodium salicylate, nabumetone

COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug.

Adapted from Bacchi, S., Palumbo, P., Sponta, A., & Coppolino, M. F. (2012). Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 11, 52-64; Warner, T. D., Giuliano, F., Vojnovic, I., Bukasa, A., Mitchell, J. A., & Vane, J. R. (1999). Nonsteroidal rug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proceedings of the National Academy of Sciences, 96, 7563-7568.

There are at least 20 different NSAID available in the United States, with formulations ranging from tablet, capsule, solution, suspension, suppository, injectable, and topical application (Table 7-2). In addition to oral formulations, acetaminophen and ibuprofen are available for parenteral administration. Diclofenac is available for topical application as a patch, gel, or solution. Aspirin, acetaminophen, and indomethacin are also formulated as suppositories. All NSAIDs are available by prescription with the exceptions of aspirin, ibuprofen, naproxen, and ketoprofen, which are also currently available over the counter (OTC) in the United States.

The availability of a topical NSAID formulation is beneficial because it reduces the likelihood of a patient experiencing adverse effects associated with systemic therapy. The topical NSAID is applied directly to the skin and it reaches only local tissue to achieve desired therapeutic effect with minimal systemic absorption (McPherson & Cimino, 2013). The most common adverse effect is local skin irritation or application site reaction, which includes dry skin, erythema, irritation, paresthesias, and pruritus. Although systemic adverse effects are less common with topical NSAIDs, patients have reported experiencing GI upset and headache (McPherson & Cimino, 2013). The topical NSAIDs available to treat painful conditions in the United States include diclofenac sodium 1% gel approved for relief of pain because of osteoarthritis

in joints such as the hands and knees that are amenable to topical treatment, diclofenac sodium topical solution 1.5% w/w in 45.5% dimethyl sulfoxide approved for osteoarthritis of the knees, and diclofenac epolamine 1.3% patch approved for topical treatment of acute pain because of minor strains, sprains, and contusions (Table 7-2) (McPherson & Cimino, 2013). The topical product should be administered directly to the desired site of action and it should be noted that the topical NSAIDs should not be used for hip osteoarthritis.

Table 7-2. Commonly Prescribed NSAIDs and Acetaminophen

Class/Drugs (Formulation)

Usual Dose (mg) (Max Dose in mg/d)



Adverse Effects

Salicylic Acids

  • Gastrointestinal (BBW)

    – Mild: nausea, heart burn, dyspepsia, abdominal pain, diarrhea in 20-40% of patients

    – Moderate: GI mucosal erosions and asymptomatic ulcers in 15-30% of patients; may heal spontaneously

    – Severe: symptomatic ulcers, with/without bleeding, can be life threatening (1-2% of users; mortality 10%)

  • Cardiovascular (BBW)

    – MI, CVA, CHF, thrombosis, sudden cardiac death

    – Greater risk with COX-2 inhibitors

  • Renal

    – Greatest risk during first 4-6 weeks

    – Acute kidney injury

    – Renal prostaglandins affect systemic vascular resistance and may lead to hypertension, sodium and water retention, edema, hyperkalemia, interstitial nephritis

    High risk:

    – ibuprofen, ketoprofen, fenoprofen, indomethacin, piroxicam

    Intermediate risk: diclofenac, sulindac

    Low risk: naproxen, nonaspirin salicylates

  • Hypersensitivity Reactions

    Lowest risk with COX-2 inhibitors


    – Anaphylaxis, severe bronchospasms within minutes


    – Acute: aspirin induced or exacerbated asthma

    – Delayed: pneumonitis

Administer NSAIDs cautiously to elderly patients with already compromised renal function, heart failure, or hypertension

Aspirin (acetylsalicylic acid) (PO, supp)

325-1,000 every 4-6 h (4,000)

0.25 h

OTC/Rx Irreversible inhibition of platelet aggregation

Diflunisal (PO)

250-500 every 8-12 h (1,500)

8-13 h

Salsalate (PO)

1,500 twice daily (arthritis)

1 h

Nonacetylated Acids

Choline magnesium trisalicylate (PO)

500-1,500 every 8-12 h (4,500)

2-3 h

Elderly: 750 every 8 h No effect on platelets

Propionic Acid Derivatives

Fenoprofen (PO)

200 every 4-6 h (3,200)

2-3 h

Flurbiprofen (PO)

50-100 twice daily to three times a day (300)

5.7 h

Ibuprofen (PO, IV)

PO: 200-400 every 4-6 h (1,200 OTC) (2,400 Rx) IV (RX only): 400-800 over 30 minutes every 6 h (3,200)

1.8-2.5 h

OTC/Rx Reversible inhibition of platelet aggregation

Ketoprofen (PO)

25-50 every 6-8 h (300)

2-4 h


Naproxen (PO)

250 every 12 h (1,000)

12-17 h

Rx only

Naproxen sodium (PO)

Acute pain: 550 every 12 h or 275 every 6-8 h (1,100)



Indomethacin (PO and Supp)

25 twice daily to three times a day

4.5 h

High risk for CNS side effect

Sulindac (PO)

150 twice daily

8-16.4 h

Pyrrolacetic Acid

Ketorolac (PO, IV/IM, nasal)

Parenteral: 30-60 IM or 30 IV initial dose; then 15-30 IV every 6 h

PO: 10 every 4-6 h

Nasal: One spray (15.75 mg) in each nostril every 6-8 h

4-7 h

Max 5 days May cause renal failure in elderly or hypovolemic patients

Phenylacetic Acids

Diclofenac potassium (PO)

Capsule: 25 four times a day

Tablet: 50 three times a day (150)

1-2 h

Diclofenac epolamine (patch)

Apply one patch twice daily to painful area

12 h

Apply only to intact skin

Diclofenac sodium (gel, solution)

Gel and solution dosing is joint specific for osteoarthritis

79 h

Indoleacetic Acid


200-400 every 6 h (1,000)

6-7 h


Piroxicam (PO)

10-20 daily

30-80 h

Meloxicam (PO)

7.5 daily (15)

16-24 h

Anthranilic Acids

Mefenamic acid (PO)

250 every 6 h (1,000)

2-3.3 h

Meclofenamate (PO)

50-100 every 4-6 h (400)

Max 7 days

Diaryl Heterocyclics (COX-2 Selective Inhibitor)

Celecoxib (PO)

200 twice daily (400)

11 h

No antiplatelet effects Contraindicated in patients with sulfonamide allergy


Acetaminophen (PO, IV, supp)

PO: 325-1,000 every 4-6 h (4,000)

IV: 1,000 every 6 h (4,000)

OTC max dose: 3,000 mg


Parenteral formulation used for postoperative pain

  • Hepatotoxicity

BBW, black box warning; CHF, congestive heart failure; CNS, central nervous system; COX, cyclooxygenase; CVA, cerebrovascular accident; GI, gastrointestinal; h, hour; IM, intramuscular; IV, intravenous; max, maximum; MI, myocardial infarction; OTC, over the counter; PO, by mouth; Rx, prescription; sup, suppository.

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Apr 16, 2020 | Posted by in NURSING | Comments Off on Pharmacologic Management of Pain
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