Caffeine: The Pain Killer Booster

Introduction

Most commonly known as a methylxanthine, caffeine is often used as a central nervous system (brain) stimulant to stay awake and increase alertness. On average more than 50% of Americans consume caffeine in coffee and beverages every day. Caffeine changes the chemistry of the brain by blocking the natural chemical that signals sleep. Caffeine acts like adenosine (brain chemical) by binding to adenosine receptors and inhibits the signal that induces drowsiness.

However, the use of caffeine is not limited to just staying alert. It is present in many products such as coffee, tea, chocolate, energy drinks and most notably analgesics (pain relievers). Caffeine has been included in medicinal products as early as 1916 when William Milton Knight created Anacin, also more commonly known as aspirin. Anacin consists of acetylsalicylic acid and caffeine with the primary use of treating pain by blocking several chemical processes that cause pain and inflammation in the body.

Since Anacin was developed and released on the drug market there have been many other medicinal products that have followed suit to include a combination of caffeine in their formula listed below.

Pain killers that contain caffeine

Cafergot (Ergotamine Tartrate and Caffeine)

Excedrin (Acetaminophen, Aspirin and Caffeine)

Fioricet (Butalbital, Acetaminophen, Caffeine)

Fiorinal (Butalbital, Aspirin, Caffeine)

Evaluation of studies of caffeine for pain management

In a recent retrospective analysis, the Cochrane Review investigated the use of caffeine as an analgesic adjuvant by evaluating results of nineteen studies. An adjuvant is an additive to medicine to increase its overall effectiveness. In its review, they compared the relative efficacy in relieving acute pain using a single dose analgesic with caffeine or the same dose of analgesic without caffeine.

The pain conditions that were evaluated included acute pain, headache, postoperative pain following childbirth or dental surgery, and menstrual period pain (dysmenorrhea). The analgesics tested in the studies were acetaminophen (paracetamol), ibuprofen, aspirin, diclofenac, and tolfenamic acid. The dose of caffeine used in the studies ranged from 50 to 260 mg. To isolate the effect of caffeine on the efficacy of pain relief, the same drug and dose combination was used with caffeine and without caffeine. Patients selected were at least 16 years old and randomized along with a double blind test to avoid bias results.

The results of the study show that adding caffeine to standard dose of analgesic such as ibuprofen boosts pain relief by 5% to 10%. The portion of patients that experience relief in pain is modestly higher with caffeine than without. The findings suggest that caffeine provides similar benefit regardless of the type of pain treated. Increasing the strength of caffeine may have no added benefit in pain relief. Over the dose range of 65 mg to 200 mg, no increase in adjuvant effect was observed when the caffeine dose was increased. This observation could be due to the small size of the studies.

The effect of caffeine combined with analgesics to boost pain relief

Ibuprofen With Caffeine (53%) Without Caffeine (42%)

Aspirin With Caffeine (26%) Without Caffeine (25%)

How does caffeine reduce pain?

The mechanism of how caffeine may enhance the efficacy of an analgesic is not clear. However, what is known is that it is a competitive antagonist of adenosine A1 and A2 receptors. Proposed mechanisms of actions listed by Cochrane Review authors and works of Renner 2007, Sawynok 1993, and Zhang 2001 include:

• Improved drug absorption through lower gastric pH and increased gastric blood flow.
• Reduced metabolic clearance of drugs through reduced hepatic blood flow.
• Blockade of peripheral pro-nociceptive adenosine signaling, and activation of the central noradenosine pathway (i.e., pain-suppressing systems).
• Transcriptional down-regulation of cyclo-oxygenase-2 COX-2), via blockade of the adenosine A2a receptor.
• Relief of inhibitor adenosine actions on central cholinergic nerve terminals.
• Changes in mood and emotional state contributing to changes in the perception of pain.

References

Diamond S, Balm TK, Freitag FG. Ibuprofen plus caffeine in the treatment of tension-type headache. Clinical Pharmacology and Therapeutics 2000;68(3):312–9.

Diamond S, Freitag FG. The use of ibuprofen plus caffeine to treat tension-type headache. Current Pain and Headache Reports 2001;5(5):472–8.

Diener HC, Pfaffenrath V, Pageler L, Peil H, Aicher B.The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre,randomized, double-blind, single-dose, placebo-controlled parallel group study. Cephalalgia 2005;25(10):776–87.

Pfaffenrath V, Diener HC, Pageler L, Peil H, Aicher B. OTC analgesics in headache treatment: open-label phase vs randomized double-blind phase of a large clinical trial.Headache 2009;49(5):638–45.

Renner B, Clarke G, Grattan T, Beisel A,Mueller C,Werner U, et al. Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. Journal of Clinical Pharmacology 2007;47(6):715–26.

Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action.Pharmacological Reviews 1993;45(1):43–85.

Zhang WY. A benefit-risk assessment of caffeine as an analgesic adjuvant. Drug Safety 2001;24(15):1127–42.

Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane Database of Systematic Reviews 2012, Issue 3.

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