Nonprescription Nonopioids

Chapter outline

Buffered Aspirin

Buffered aspirin has been compared with nonbuffered aspirin, and endoscopic evaluation shows no difference in the amount of gastric damage produced by either one. Enteric-coated aspirin does not decrease the incidence of local irritation either (Bhatt, Scheiman, Abraham, et al., 2008; Laine, 2001). Nevertheless, some individuals report less dyspepsia and prefer these formulations.

Caffeine

Caffeine has been used to augment pain relief since research in the early 1980s showed that it produced a 40% acetaminophen dose-sparing effect (Zhang, 2001). Other research found that caffeine in combination with acetaminophen (but not alone) produced a significant enhanced and prolonged analgesic effect with onset of analgesia within 30 minutes and lasting for up to 3 hours (Renner, Clarke, Grattan, et al., 2007). Caffeine produces a synergistic effect with a variety of other analgesics as well, including opioids and NSAIDs (Diamond, Freitag, 2001; Mitchell, van Zanten, Inglis, et al., 2008). Consumption of caffeinated coffee has even been found to enhance the analgesic effect of nicotine (Nastase, Ioan, Braga, et al., 2007) (see Section V for more on nicotine analgesia). The underlying mechanisms of caffeine’s action are unclear, but theories include that it blocks adenosine receptors, inhibits COX-2, or simply changes emotional state (Zhang, 2001).

Caffeine is often combined with nonopioids for the treatment of migraine and tension-type headaches. Combinations produce better pain relief than any of the analgesics alone for this type of pain (Diamond, Balm, Freitag, 2000; Diamond, Freitag, 2001). Research has not confirmed the optimal dose of caffeine for increasing the analgesia of nonopioids, but the minimal effective dose appears to be 65 mg (APS, 2003; Zhang, 2001). While nonopioid analgesia may be enhanced with this amount of caffeine, patients often also experience dizziness and nervousness (Zhang, 2001).

A randomized controlled study found that a single dose (2 tablets) of the combination of aspirin (250 mg), acetaminophen (250 mg), and caffeine (65 mg) produced significantly better and faster pain relief than a single dose of ibuprofen (200 mg) or placebo for acute migraine (Goldstein, Silberstein, Saper, et al., 2006). In contrast, a study of patients following outpatient general surgery found that acetaminophen plus ibuprofen produced fewer adverse effects and higher patient satisfaction than the combination of acetaminophen, codeine, and caffeine (Mitchell, van Zanten, Inglis, et al., 2008). However, the difference in findings in this study may have been due to codeine, which is associated with a relatively high incidence of adverse effects and wide variability in efficacy due to dependence on CYP2D6 metabolism; 10% of Caucasians are poor metabolizers and derive little or no analgesia from codeine (Stamer, Stuber, 2006) (see Chapter 13 for more on codeine). Other research supports the use of caffeine in the postoperative setting; randomized-controlled trials and an extensive meta-analysis of 30 trials concluded that caffeine significantly enhanced postoperative pain relief when combined with other analgesics (Fitzgerald, Buggy, 2006). Despite this evidence, caffeine is rarely prescribed as a component of a postoperative multimodal analgesic regimen.

IV caffeine has been researched in advanced cancer patients experiencing adverse psychomotor effects associated with high doses of opioids and found to have little effect (Mercandante, Serretta, Casuccio, 2001). Pain significantly decreased, but this was not statistically superior to placebo. Caffeine produced improvements in speed of finger tapping, but there was no improvement in cognitive outcomes as measured by testing of visual memory and number and digit recall. (See Section V for use of caffeine to counteract opioid-induced sedation.)

Because caffeine is a CNS stimulant, its effect on the cardiovascular (CV) system has been a concern. Some adults are very sensitive to caffeine and respond to even small doses with tremors, increased heart rate, and insomnia. Individuals with CV risks must exercise caution in the amount of caffeine they consume or avoid it altogether. For most people, moderate intake of caffeine (e.g., 200 to 300 mg, which is more than the amount required to augment nonopioid analgesia) is considered safe (Mayo Clinic.com, 2008). Heavy use (500 to 600 mg/day; 5 to 7 cups of coffee/day) is associated with a significant increase in adverse effects. Chronic repeated exposure to caffeine can increase the risks for development of analgesic-overuse headache, chronic daily headache, and physical dependency (Shapiro, 2008). Discontinuing caffeine after long-term use can lead to a withdrawal syndrome with headache as a dominant symptom.

An inexpensive way to reap the benefits of a caffeine/nonopioid combination is to avoid commercially compounded preparations and simply buy generic forms of the ingredients separately (e.g., aspirin and acetaminophen) and ordinary caffeine-containing beverages as a source of the dose of caffeine required for enhanced analgesia. Individuals often report resolution of pain, particularly headache pain, after drinking caffeinated beverages. Stimulant products also often contain a sufficient amount of caffeine (e.g., No-Doz has 200 mg caffeine).

A variety of food products contain caffeine. Chocolate lovers may be dismayed to learn that most chocolate contains very little caffeine (e.g., 9 mg). However, 1.45 ounces of dark, semisweet chocolate contains 31 mg, requiring at least 3 ounces to obtain the desired analgesic effect. The popularity of energy drinks, which contain large amounts of caffeine (e.g., 300 mg), has prompted calls for changes in labeling to include stronger warnings of the dangers of excessive caffeine intake (Johns Hopkins Medicine, 2008). See Table 9-1 for the caffeine content of common beverages, food, and over-the-counter (OTC) drugs.

Antihistamines

As discussed early in Section I, histamines promote pain transmission (Raffa, 2001). Further research is needed to clarify the underlying mechanisms, but three histamine receptors appear to be primary sites of action. The antinociceptive properties of morphine were enhanced in H₁ and H₂ receptor knockout mice (H₁ and H₂ receptors are genetically “turned off”) indicating a role (Mobarakeh, Takahashi, Sakurada, et al., 2006). The analgesic action of the centrally-acting nonopioid nefopam was modulated by H₃ receptors but not H₁ and H₂ receptors in other animal research (Girard, Pansart, Coppe, et al., 2004).

Despite histamine’s role in nociception, antihistamines are poor pain relievers, and there is little evidence to support common claims of enhanced pain relief and dose-sparing effects when they are combined with other analgesics (APS, 2003; Fitzgerald, Buggy, 2006). For example, very little research could be found to support the use of antihistamines for analgesia in the postoperative setting; however, the phenothiazine-derived antihistamine promethazine (Phenergan) is commonly used in the postoperative setting based on a misconception that it potentiates opioid analgesia (APS, 2003). One study of patients following abdominal hysterectomy showed that those who received preoperative promethazine (0.1 mg/kg) consumed less postoperative PCA morphine than those who received the same dose of the drug postoperatively (Chia, Lo, Liu, et al., 2004). However, another study found no differences in opioid-sparing effects among patients following abdominal hysterectomy who were randomized to receive different amounts of diphenhydramine (Benadryl) or placebo at induction plus morphine PCA postoperatively (Lin, Yeh, Yen, et al., 2005).

The use of antihistamines in the postoperative setting, where patients are given anesthesia and other sedating medications, may be dangerous because it can produce an additive sedative effect and increase the risk of respiratory depression (Anwari, Iqbal, 2003). Patients must be watched very closely and antihistamine administration discontinued if increasing sedation is detected (see Chapter 19).

Antihistamines, such as phenyltoloxamine and diphenhydramine, are commonly combined with nonopioids, such as acetaminophen, aspirin, and ibuprofen, and promoted as night-time pain relievers (Table 9-2). Occasionally, antihistamines are administered for bone pain associated with chemotherapy-induced neutropenia when other strategies are ineffective; however, research is lacking on this approach (Pangilinan, 2008).

Conclusion

Analgesics available without a prescription (OTC) include many formulations and brands of aspirin and acetaminophen as well as ibuprofen, naproxen, and ketoprofen (see Tables 9-2 and 9-3) (see also Patient Medication Information Forms III-4 and III-5 on pp. 256-259). More NSAIDs are likely to become available as OTC analgesics. Clinicians need to be familiar with doses and ingredients of those used by the individual patient. Clinicians also should know that sometimes a nonprescription NSAID (e.g., ibuprofen) will be less expensive than the same dose by prescription.