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Anesth Pain Med. 2016 June; 6(3):e33193. doi: 10.5812/aapm.33193.

Published online 2016 March 26. Review Article

The Role of Caffeine in Pain Management: A Brief Literature Review
Alireza Baratloo,1 Alaleh Rouhipour,2 Mohammad Mehdi Forouzanfar,1 Saeed Safari,1 Marzieh Amiri,3
and Ahmed Negida4,*
Department of Emergency Medicine, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Pediatric Specialist, Tehran, Iran
Department of Emergency Medicine, Shahid Beheshti Hospital, Guilan University of Medical Sciences, Anzali, Iran
Student Research Unit, Zagazig University, Zagazig, Egypt
Corresponding author: Ahmed Negida, Student Research Unit, Zagazig University, Zagazig, Egypt. Tel: +20-1150333699; +20-1125549087, E-mail:

Received 2015 September 15; Revised 2015 October 17; Accepted 2015 October 20.


Context: Caffeine is the most commonly used psychoactive legal drug in the world. Caffeine’s role in controlling pain has received
less attention in the past, yet is being increasingly considered. This article briefly reviewed the literature to clarify the role of caffeine
as a drug for pain control and attract investigators to this topic.
Evidence Acquisition: The data on Caffeine as an adjuvant therapy or as a main component for pain modulation has been narra-
tively reviewed.
Results: Caffeine plays an important role in pain modulation through their action on adenosine receptors which are involved in
nociception. The use of caffeine as adjuvant treatment was well-established in the literature and caffeine is currently available in
some over the counter medications. Studies showed controversial results about the interaction between caffeine and morphine
for pain relief in patients with terminal stage cancer. As a main component for pain modulation, Caffeine can be used for hypnic
headache and postdural puncture headache.
Conclusions: Caffeine has a potential role for pain modulation. Current evidence on caffeine use for migraine and terminal stage
cancer is not well-established. Future studies should address the use of caffeine alone for different types of pain with dose escalation
and standardization of outcome measurement.

Keywords: Caffeine, Adenosine, Role, Pain Management

1. Context
short-term health effects. On the other hand, there has
not been a lot of research on caffeine, so the risks could
1.1. Brief History of Caffeine
be underestimated (5, 6). Consumption of moderate
Caffeine is an alkaloid named “3,7-dihydro-1,3,7- amounts of caffeine is safe for healthy non-pregnant
trimethyl-1H-purine-2,6-dione”, with its chemical structure adults. It increases energy, alertness, wakefulness, the
presented in Figure 1. Caffeine is a psychoactive and central accuracy of reactions, and the ability to concentrate and
nervous system stimulant of the methylxanthine class, focus attention and decreases fatigue. It also enhances
that unlike many other psychoactives, is legal all around physical performance, short-term memory and cognitive
the world (1). Based on some historical documents, caf- performance (6). Caffeine’s role in controlling pain is one
feine effects were noticed by a goat herder named Khaldi of the aspects, which has been less considered in the past
in southern Abyssinia in the year 850, yet it was extracted yet is being increasingly considered. This article briefly
for the first time by a German chemist named “Friedlieb reviewed the literature to clarify the role of caffeine as
Ferdinand Runge” in 1819 (2, 3). Drinks containing caffeine a drug for pain control and attract investigators to this
such as tea and coffee became widespread in the 15th and topic.
16th centuries in Arabian countries and in the 18th and 19th
centuries in Europe. Nowadays, many people start their 2. Evidence Acquisition
day with a cup of coffee. It seems that caffeine’s medical
effects had been known long before it became a part of In this review, we searched PubMed using this query
regular daily drinks (4). Based on the available scientific “Caffeine AND Pain”. Relevant studies were identified and
evidence, caffeine seems to have minor health risks yet data on caffeine role as an adjuvant therapy and as a main
its long-term benefits outweigh the potentially negative component for pain modulation was narratively reviewed.

Copyright © 2016, Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM).. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in
noncommercial usages, provided the original work is properly cited.

may explain caffeine antinoci- ceptive effects and its adjuvant actions (11. adjuvant analgesic effects since decades ago (23. first we must be familiar with a substance significant (22. doses of caffeine to a standard dose of common analgesics narios. Role of Caffeine as an Adjuvant Component in Pain Man- agement An adjuvant component is something that is added to a medicine to enhance its effectiveness (22). Derry et al. intravenous infusion once a day for two days as an adjuvant feine does not alter dopamine release and therefore does to opioid for pain management in patients with advanced not have abuse potential like other adenosine blocking cancer. concentration and vigilance. Chemical Structure of the Caffeine Molecule caffeine are present as an adjuvant in combination with antidepressant. which added 100 . postoperative dental pain and postpartum pain sine receptors in human bodies including A1. Some reviews found that adding low Pain management has been studied with various sce. The endogenous compound adenosine has various their authors claimed that adding 100 mg of caffeine or modulatory effects in the central and peripheral nervous more to an analgesic could be useful (22. caf. systematic review performed by Derry et al. 25). 24). Before addressing the role of caffeine strated that the mentioned effect was small yet statistically in pain control. 2 Anesth Pain Med. Despite this. 25). and it is still being investigated (7-10). Caffeine’s enhances pain relief in a small yet important proportion role in pain management is among questionable yet attrac. systems and its receptors have been known to be involved in antinociception. 14. 6(3):e33193. Following a tive subjects in this regard.1. acetaminophen and non-steroidal anti- inflammatory drugs in many over the counter (OTC) anal- Experts from emergency department at Shahid Beheshti gesics. Headache. Clinical studies have tested and demonstrated its University of Medical Sciences were consulted about rele. some researchers claim that genetics can influ- ence the response of individuals to caffeine consumption (21). Baratloo A et al. Its in- vant studies on caffeine and pain management. such as cocaine. nociceptive and inflamma- tory models (12-14). nervous system (PNS). leads sion significantly reduced pain and drowsiness. Caffeine for Pain Management bition of cyclooxygenase activity. Enhancing these receptors could lead Despite what has been said. hibitory effects on A2A and A2B receptors. 2016. . volving 7238 participants). 18-20). They assigned 20 patients to the caffeine group and 21 to the placebo group. There are four subtypes of adeno. Caf- feine could reduce pain sensation through its effects on duction did not reach clinical significance in patients with advanced cancer undergoing opioid therapy (26). have been raised to ex- plain these effects (11). The effects of caffeine on pain control are somewhat complex yet understanding such ef. as well as inhi- 2. Antagonism of adenosine receptors. Low doses of Figure 1. yet the re- to renewed interest as a novel option for pain control. found 19 eligible studies (in- called adenosine. They concluded that caffeine infu- agents. adenosine receptors (14-18). caffeine in combination with morphine. It was discovered hibition or augmentation depending on the disease and that activation of A1 and A2A receptors leads to antinoci- the amount and route of administration (11). Adenosine is an inhibitor of neuronal ac. compared to the analgesic alone. The structure of caffeine is similar to in South Korea ran a double-blind randomized. A2B. Results 3. results in complex outcomes including in- to arousal. Caffeine seems to express its direct effect via central blocking of adenosine receptors that influence pain signaling or by blocking of peripheral adenosine receptors on sensory afferents. Understanding these effects.130 mg of caf- tivity in the central nervous system (CNS) and peripheral feine to the main drug such as ibuprofen or paracetamol. 3. as well as inhibition of cyclooxyge- nase activity at some sites. A3.1. it was demon- fects is valuable (11). In- terestingly. placebo- adenosine and therefore Caffeine compete with adenosine controlled trial to assess the efficacy of 200 mg of caffeine for A2a receptors causing their inhibition. Researchers ception in neuropathic pain. A2A. of patients. and were more prevalent conditions that have been evaluated. which are expressed in different parts of the CNS and No serious adverse event was reported in these studies and PNS.

tion. the difference between short and long acting analgesics. yet is being increasingly Postdural puncture headache (PDPH) is frequently re- considered. also conducted a vising the manuscript: all authors. It was reported that caffeine. feine administration is a noninvasive and safe option that ment may prevent the use of invasive methods such as epidural Hypnic headache is a rare benign primary headache blood patching. in- sisted of case reports or smaller open case series. caffeine leads to fore. Role of Caffeine as the Main Component in Pain Manage. 35). data synthesis and drafting manuscript: all authors. It should be noted that based on the current evidence. 6(3):e33193. There. On the other hand. patients with PDPH and assessed the pain scale immedi. claimed that administrating intravenous caffeine sodium benzoate during and after spinal anesthesia could mini. later. it is generally recommended to use these compounds augmentation of cerebrospinal fluid production by stimu- on a temporary basis for acute pain control (24). Most investigators recommend caffeine as a therapeutic option for treatment of this type of headache. caffeine landed a more promi- in 2004 within the “other primary headache” group (code nent role as a treatment option. After new findings about by the international classification of headache disorders migraine pathophysiology. disorder. ature to clarify the role of caffeine as a drug for pain con- tively common after spinal anesthesia. 2016. ceived less attention in the past. They Authors’ Contribution: Study concept and design. For instance. They concluded that oral caffeine could be consid- use of analgesics containing caffeine may be associated ered for pain relief in PDPH (38). Caffeine has the ability to cross the blood-brain barrier.2. sumed to be a consequence of CSF leakage into the epidu. receptors. et al. or epidural injection of NaCl 0. It seems that caf- 3. Baratloo A et al. re- mize the rate of PDPH (39). 28).5) (27. proofreading: Ahmed double-blind. It was first described in 1988 by Raskin. The hallmark of PDPH is decreased pain score in investigators could explore. Camann et al. ulty members of the emergency department of Shahid Be- tration and dosage. In a pilot study performed in 2014. could be an effective treatment option for this type of headache.9% (35. 3 . feine. We would like to express our special thanks to the fac- ies have been conducted with different roots of adminis. physical dependence. commonly affecting middle-aged patients at Caffeine is frequently used as an adjuvant therapeutic night. selection of relevant studies: all authors. yet it has been as. and the authors were responsible for all expenses. The investigators randomly administered 1000 mL of normal saline with 500 mg of caffeine sodium Footnotes benzoate or 1000 mL of normal saline during the first 90 minutes after spinal anesthesia administration. By blocking adenosine with overuse headache. Alireza Baratloo. it seems travenous administration of 60 mg of caffeine citrate for 61 that caffeine can be used as a first line agent for acute treat- patients affected by acute migraine attack. 40). has not been considered. and leads to a decrease in cerebral blood inflow and brain blood volume. the supine position and its increase in the upright position (34. lating sodium-potassium pumps (35. was reported as ment in this type of headache. Therefore. or with. placebo-controlled trial in this regard. 4. Postdural puncture trol and attract investigators to this topic. caffeine is added as an adjuvant. Many stud. intramuscularly and intravenously (36). and adopted agent for migraine headache. performed a double-blind randomized clinical trial on this topic. Anesth Pain Med. and act as a vasoconstrictor 4. The current article briefly reviewed the liter- ported as a complication of lumbar puncture and rela. Yucel heshti University of Medical Sciences. caffeine increases cerebral arterial vasoconstric- drawal symptoms upon abrupt discontinuation. An appro. Caffeine was first prescribed as a treatment agent for PDPH in 1949 and some investigators have orally used it Acknowledgments at different doses. Funding/Support: All authors declared that this study ately before drug administration and four and 24 hours was accomplished without any funding or support. department (42). 38). there are many topics in this regard that willing ral space. when headache pathogenesis is still doubtful. They administered 300 mg of oral caffeine to forty postpartum Negida. and also as a prophylactic agent as well. 41). Based on a literature review that only con on cerebral vessels. even in a cup of a safe and well-tolerated abortive option at the emergency strong black coffee or using OTC analgesics containing caf. Conclusions priate randomized clinical trial is still needed to confirm Caffeine’s role in pain control is a subject that has re- such claims (29-33). and varying success rates (37. Some authors even believe that dramatic re- sponse to caffeine can be considered as pathognomonic clinical feature in diagnosis of hypnic headache.

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