Which analgesics can be taken together

Mixing any opioid painkillers with alcohol or tranquilisers means that having an overdose is more likely. This can cause a coma, breathing problems and in some cases, death. People can build a tolerance to opioid painkillers.

This means that you have to take more of them to get the same effect or avoid withdrawal symptoms. Because of this, they may not be suitable for treating long-term pain. Withdrawal symptoms are physical or psychological reactions that happen when you stop taking a drug that you are addicted to. It is illegal in England and Wales to drive when taking prescription drugs if this affects your ability to drive.

Some people need to take more than one type of painkiller at any one time. If you need to do this, you need to be aware of drug combinations that are safe and unsafe. Speak to your doctor if you have any questions or concerns about the types of painkillers you have been advised to take.

Many people with arthritis and related conditions will need to take painkillers or NSAIDs, along with drugs that treat the underlying cause of their condition. The combination you take will depend on your condition. For inflammatory types of arthritis, such as rheumatoid arthritis , your doctors should recommend disease-modifying anti-rheumatic drugs DMARDs. These types of drugs change how your condition develops. If you have gout , you may need NSAIDs or colchicine coal-chuh-seen to deal with the pain and swelling from an attack.

You may then need another drug, such as allopurinol al-oh-pure-ri-nol or febuxostat fe-bucks-oh-stat , in the longer term to reduce the risk of having more gout attacks. If you have pain as a result of nerve damage, or fibromyalgia fie-bruh-my-al-juh your doctor may suggest drugs such as amitriptyline am-ee-trip-ter-leen , gabapentin gab-a-pen-tin or pregabalin prey-gab-a-lin.

Although these are not classed as painkillers, they can be helpful for some types of pain. If you have osteoarthritis of the hand or knee , topical capsaicin cap-say-sin applied several times daily can be used alongside other painkillers. If you're taking any other medications speak to your doctor or a pharmacist about possible interactions. Talk to your doctor or a pharmacist if you have any concerns.

There may be a small increased risk of miscarriage if NSAIDs are taken around the time of conception. You may therefore wish to avoid NSAIDs if you are trying to conceive and during the first three months of your pregnancy.

Low-dose aspirin may be continued during your pregnancy and is recommended if you have:. There is little evidence on the use of newer NSAIDs, called cox-2 inhibitors during pregnancy, so these should be avoided. Paracetamol and opioid painkillers may be used during pregnancy, although it is recommended that you do not use them regularly or for long periods.

Caution is advised with drugs containing codeine, as it could affect the nervous system of the unborn baby. Regularly taking high doses of opioid painkillers while pregnant in the lead up to birth can cause the baby to have withdrawal symptoms. If you do, it could increase your risk of premature labour or a miscarriage. Paracetamol and aspirin can be taken while breastfeeding. Find out more about how arthritis symptoms may change with pregnancy and advice on taking medication.

Opioid painkilling patches are used to treat some types of long-term pain. Learn more about how to use these patches and potential side effects. Print this page. Analgesics are a class of medications designed specifically to relieve pain. They include acetaminophen Tylenol , which is available over the counter OTC or by prescription when combined with another drug, and opioids narcotics , which are only available by prescription.

There are two types of opioids: conventional or atypical. They work differently in the body. Some medicines combine acetaminophen with an opioid for added pain relief. But two opioids should never be taken together. The use of opioids for chronic, non-cancer pain is controversial.

But the drugs are an important treatment option for people with uncontrolled arthritis pain, particularly if they cannot take nonsteroidal anti-inflammatory drugs NSAIDs. Because of potential for side effects and accidental overdoses, opioids are tightly regulated. Benefits and Risks Analgesics can be life-changing for people with arthritis, relieving pain and making it possible to work, do daily activities and maintain a level of activity needed for good health.

But they also carry risks, particularly if not used carefully. Acetaminophen Acetaminophen is the active ingredient in more than OTC and prescription medications. These include products for cold, allergy, headache and sleep. Benefits: For many people, acetaminophen provides pain relief without the stomach upset and other common side effects of NSAIDs.

When taken according to instructions on the label, it is generally safe. When taken in too-high doses or along with alcohol, it can cause severe liver damage, which can be fatal.

They work by binding to receptors on cells mainly in the brain, spinal cord and gastrointestinal system. Atypical opioids were developed to relieve pain with less risk than conventional opioids. They work in different ways, but their effects on pain are similar to conventional opioids.

This makes them particularly beneficial for acute pain, such as the pain from surgery, a broken bone or an acute flare of arthritis. Risks: Over time, your body develops a tolerance for opioids.

That means it takes larger doses of the drugs to achieve the same results. By acting on pain receptors in the brain, opioids slow breathing. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Special Issues. Article Sections On this page References Copyright. Received 29 Apr Accepted 29 Apr Published 11 Jun References R. View at: Google Scholar A.

Li Wan Po and W. View at: Google Scholar H. This antinociceptive system includes areas in the anterior cingulated cortex, hypothalamus, periaquaductal grey area, and rostral medullar area as well as descending pathways to the dorsal spinal horn. Activity in these areas can be connected to the effects seen in placebo and nocebo responses [ 5 ]. This diversification of the pain system also explains why a wide range of different molecular substances can be used in the treatment of different pain states.

Specific drugs directed at individual molecular targets are often found to be less effective at treating disease or disease symptoms than multi-target therapeutics. This particularly applies in the case of pain therapy. It would appear that the tendency, which was prevalent in the past, to view cellular causation as conforming to simple linear patterns in which macro-scale effects are specified by micro-scale structures [ 6 ] needs to be revised.

The complexity of the molecular-biological mechanisms requires precise multi target modulation [ 7 ]. The limitations of many monotherapies can be overcome by attacking the disease system via multiple pathways [ 8 ]. In many important therapeutic areas such as diabetes, infectious disease, asthma, hypertension, depression, anxiety disorder, cancer pain therapy, and, as discussed here, pain therapy, multi-component drugs are now standard [ 9 ].

In this article, we describe the scientific evidence for the superior efficacy of fixed-dose combinations [ 10 ] and discuss their role in the pharmacotherapy of pain and particularly of headaches. It is important to note that the distinction between a single drug with a single pharmacological activity and a combination drug with combined pharmacological activities is not absolute [ 11 ].

It is known from various analgesics and NSAIDs non steroidal anti inflammatory drugs that different mechanisms of their analgesic effect are discussed in the most diverse of pain models e. Moreover, ibuprofen assumes an intermediate position between a single drug with a single pharmacological activity and a combination drug insofar as a racemate is concerned, i.

However, in general a combination therapy or a multi-target approach is understood as a combination of two or more active pharmaceutical ingredients [ 10 ] with complementary mechanisms of action, which extends the range of therapeutic options in the treatment of almost every human disease [ 11 ].

The fixed combination of indomethacin a potent, non-selective inhibitor of cyclooxygenase enzymes , prochlorperazine a phenothiazine antiemetic with analgesic properties , and caffeine a methylxanthine, and an effective analgesic adjuvant , has been a frequently used medication for the acute treatment of migraine and tension-type headache TTH in Italy for over 30 years [ 15 ]. In experimental animal models, this combination had an antihyperalgesic activity that was significantly superior to that of its single components [ 16 ].

The fixed combination was able to abolish the peripheral sensitization induced by kainic acid and the central sensitization induced by N-methyl-D-aspartate NMDA in in vivo models of hyperalgesia, while sumatriptan was not able to reverse either the kainic acid-induced or the NMDA-induced hyperalgesia [ 17 ].

In a mice model of the abdominal constriction test, the fixed combination and sumatriptan at analgesic doses exerted their central antinociceptive action independently of the Gi proteins, and the efficacy of the combination was statistically superior to that of sumatriptan [ 18 ]. In a double-blind, double-dummy, randomised, parallel group, multicenter study, the fixed combination and sumatriptan 50 mg did not significantly differ in the acute treatment of migraine attacks in terms of the primary efficacy endpoint [ 15 ].

In a similar study on the treatment of episodic tension-type headache, the fixed combination was significantly superior to the control substance nimesulide a sulfonamide compound with antiinflammatory, analgesic and antipyretic effects at mg in the second headache episode, but not in the first episode examined [ 19 ].

Although the introduction of triptans in the s opened up a new therapeutic option in particular for migraine, in a publication entitled "Beyond monotherapy: rational polytherapy in migraine" in , Peroutka [ 20 ] pointed out that, although monotherapeutic approaches are effective in many migraineurs, they do not provide rapid, consistent and complete relief in all of them.

Using the pharmaceutical prescriptions database of two consecutive years in a regional Health Authority in Italy, a low percentage of triptan users and a low rate of utilization, associated with a high percentage of discontinuation and new utilization, were observed, without any substantial increase in triptan utilization over the years. All of these data probably do not support optimal satisfaction with triptan therapy [ 21 ]. This confirms data from the southern district of "Clalit health services," a large Israeli HMO Health Maintenance Organization , showing that many migraine patients choose not to use triptans after their first experience with the drug [ 22 ].

Therefore, if monotherapy is suboptimal, it logically follows that concurrent therapy i. Krymchantowski agrees with this and, on the basis of a whole series of clinical studies Table 1 , calls for "breaking the paradigm of monotherapy" [ 23 ]. From a retrospective clinical case series, the observation was made that in migraine patients for whom headache recurrence within 24 h frequently occurred following attack treatment with sumatriptan, the combination of sumatriptan with an NSAID tolfenamic acid mg led to a reduction in the recurrence rate [ 24 ].

This reduction in the recurrence rate was also shown for the combination of sumatriptan with naproxen sodium in an open-label study [ 25 ]. These observations were confirmed in randomized controlled clinical trials, which demonstrated that multimechanism acute therapy for migraine, combining a triptan sumatriptan and an analgesic naproxen sodium offers improved clinical benefits over monotherapy with these selected standard antimigraine treatments [ 26 ].

The benefit of this combination existed not only in the lowest headache recurrence rate but also in significantly superior pain relief 2-hour pain response [ 26 ]. In two further clinical studies, the fixed combination of sumatriptan 85 mg plus naproxen sodium mg as a single tablet resulted in more favourable clinical benefits compared with either monotherapy [ 27 ]. The consistency of these benefits over multiple migraine attacks was recently shown in two further clinical studies [ 28 ].

Such a benefit was also shown in an open-label study on the combination of rizatriptan with the COX-2 inhibitor rofecoxib. The combination reduced recurrence rates compared to rizatriptan monotherapy, [ 29 ].

A similar result was shown for the combination of rizatriptan and tolfenamic acid, a traditional NSAID [ 30 ]. In addition, acetaminophen has been assessed as part of combination therapy with rizatriptan [ 32 ]. The combination proved superior to both acetaminophen and placebo, but failed to achieve superiority over rizatriptan alone, which the authors attributed to the low number of cases and consequently insufficient power [ 32 ]. Therefore, Krymchantowski and Bigal conclude that recent evidence that has been gathered on combination therapies utilizing rizatriptan plus NSAID and even gastrokinetic drugs, such as trimebutine, point to a future of more effective combined therapy for migraine [ 34 ].

Even though the clinical data are still limited at present, it can nevertheless be stated that a multi-target combination therapy with a triptan plus an NSAID is more effective in acute migraine treatment than monotherapy with either drug alone.

This superior effectiveness relates not only to a more successful avoidance of headache recurrence, but equally to superior pain relief 2-hour pain response. These observations are in good agreement with the basic scientific results showing that in the course of a migraine attack not only triptan responsible processes like activation of 5-HT 1D receptors take place but also an up-regulation of cyclooxgenase 2 can be detected [ 36 ].

The use of multi-target pain therapeutics in the treatment of migraine is not new. Ergotamine tartrate has typically been prescribed as a combination agent with caffeine and other adjunctive therapeutic agents [ 32 ].

Caffeine has been used in combination with mild analgesics for many decades, with its utility deriving from its adjuvant properties. Sawynok and Yaksh [ 37 ] presented a review of data from 27 clinical studies in which caffeine was examined in combination with antipyretic analgesics and found that there are only a few investigations that have defined caffeine actions as an analgesic when given alone [ 37 ].

In a study by Camann et al. However, these clinical trials were criticized due to their small sample size, methodological weaknesses and conflicting results, or invalid answers [ 40 ]. Ward et al. Myers et al. The effectiveness of caffeine mg as an analgesic adjuvant to ibuprofen mg or mg was demonstrated by evaluating the ibuprofen-caffeine combination in the treatment of postoperative pain after removal of third molars [ 43 ].

Caffeine 50 mg, mg, mg increased the analgesic effect of ibuprofen mg. There was also an earlier onset of analgesic effect, as was shown in another study third molar extraction [ 44 ].

There were no significant differences between the three caffeine treatments. A superior efficacy of the combination of ibuprofen mg and caffeine mg compared to ibuprofen mg alone, caffeine mg alone and placebo was shown in a study in patients with tension-type headache [ 45 ].

However, it should be noted that all these studies had methodological limitations, in that the primary endpoint was not defined a priori, and the significance level was not adjusted for multiple testing. A double-blind cross-over pilot study evaluated the effect of ibuprofen mg, dosage was selected depending on body weight and caffeine mg compared with ibuprofen and placebo in 12 children with headaches.

Although this small pilot study was not sufficiently powered to prove any statistically significant benefit for caffeine with ibuprofen, the study did show a trend toward a superior efficacy of the combination vs. The results of a clinical study suggest that the combination of diclofenac sodium mg and caffeine mg is also more effective than diclofenac sodium mg alone in the acute treatment of migraine [ 47 ]. Caffeine has been found to accentuate the analgesic effects of acetaminophen and ASA in a broad collection of pain states such as tension-type and migraine headaches, dysmenorrhoea, cancer pain, postpartum pain, sore throat, and dental postsurgery pain.

For example, the combination of paracetamol mg and caffeine mg was significantly more effective than paracetamol alone in the treatment of tension-type headache [ 48 ]. Paracetamol mg combined with caffeine mg was found to be an effective treatment for primary dysmenorrhoea.

Here caffeine acts as an analgesic adjuvant and enhances the efficacy of paracetamol [ 49 ]. In an experimental human pain model based on pain-related cortical potentials after phasic stimulation of nasal mucosa with CO 2 and pain ratings after tonic stimulation with dry air, the combination of paracetamol mg with caffeine mg was shown to be significantly superior compared to paracetamol mg or caffeine mg alone in reducing perceived pain throughout the whole measurement period [ 50 ].

Paracetamol absorption was accelerated by caffeine, which confirms earlier findings [ 51 ]. In the same pain model, it had already been shown previously that caffeine mg enhances the analgesic activity of propyphenazone mg [ 52 ]. In the treatment of tension-type headache, the combination of paracetamol mg with caffeine mg was significantly superior to placebo [ 53 ].

ASA mg in combination with caffeine 65 mg was statistically superior to ASA alone in postoperative oral surgery pain [ 54 ], and ASA mg combined with caffeine 64 mg was superior to ASA as a monotherapy in sore throat pain [ 55 ]. A logical consequence of the arguments discussed above is that not only the combination of two substances was introduced but also the fixed combinations of caffeine with two analgesics were investigated.

A meta-analysis of the effect of caffeine in combination with ASA and paracetamol involving more than 10, patients was conducted [ 56 ]. Although most studies included patients with postpartum uterine cramping or episiotomy pain, some comprised patients with pain from oral surgery or headache. The overall pooled relative potency estimate of 26 clinical dose-finding studies was 1. The optimal dose ratio of ASA: paracetamol: caffeine was found to be 1: 1: 0.

Criticism was levelled at Diener et al. However, this disregards the fact that in this study, the comparison was not with the dosage of the individual active ingredients in the combination here mg ASA, mg paracetamol , as is usual in studies designed to prove the combination rationale. Rather, the comparison was with the highest permitted dosage of mg ASA or mg paracetamol. Nevertheless, the combination still proved to be significantly superior in terms of its analgesic effectiveness.

From the perspective of the drug regulatory authorities, "self-medication must have a low level of toxicity and low risk of serious adverse reactions. Clinically significant interaction with other commonly used medicines or major prescribed drugs must be avoided.

The nonprescription medicine must present no indirect danger, e. As early as , caffeine in this combination was evaluated by the Non-Prescription Drug Advisory Board of the FDA as a category 1 analgesic adjuvant "recognized as safe and effective" [ 64 ]. This evaluation corresponds to that of the German regulatory authority, the BGA Bundesgesundheitsamt; German Health Authority , which was published in the form of two monographs in the "Bundesanzeiger" the German Federal Gazette [ 65 , 66 ].

In spite of this, allegations have been repeatedly made in relation to caffeine-containing analgesics, with claims of an increased risk of nephropathy, and an induction or maintenance of increased or frequent use of these analgesics that does not comply with regulations.

This is highly surprising, as three detailed analyses of the epidemiological studies [ 67 — 69 ] upon which the allegations of an increased risk of developing nephropathy were based showed, independently of one another, that these data do not conclusively establish a causal link between use of specific analgesics and chronic renal failure [ 68 ].

Bach et al. They add that there are no epidemiological data that implicate caffeine in analgesic-associated nephropathy [ 67 ]. In their analysis, Feinstein et al. Thus, Feinstein et al. In the subsequently implemented autopsy study in Basel, based on over consecutive autopsies, Mihatsch et al. The epidemiological case-control study conducted upon the suggestion of Feinstein et al. Of the cases, the 22 cases with the highest analgesic intake were evaluated individually, resulting in the conclusion that data supporting the existence of such an analgesic-associated nephropathy AAN are, however, not consistent and most likely due to confounding by indication [ 73 ].

These findings were supplemented by a prospective cohort study Physicians' Health Study , which showed that no association was observed between analgesic use and reduced creatinine clearance as a marker for renal dysfunction [ 74 ]. Even if it can be assumed on the basis of theoretical considerations, an independent potential of abuse of caffeine in combination with ASS paracetamol is not substantiated by the scientific findings [ 65 , 66 ].

Thus, in answer to the question "does caffeine contribute to overuse or abuse of analgesic products? Nevertheless, caffeine coformulated with analgesics has been repeatedly accused, particularly by nephrologists, of inducing or sustaining analgesic overuse. A detailed analysis of the original publications behind the numerous literature citations shows that the epidemiological studies do not provide convincing evidence for a role of caffeine in prompting excessive analgesic use.

Moreover, the identified groups of nephrologists did not provide substantial data to advocate the said suspicion, except for the observation of a preferential choice of phenacetin-containing combinations, especially powder preparations [ 77 ].

The fact that phenacetin, which was used exclusively in the form of combination analgesics often in conjunction with caffeine , is the sole antipyretic analgesic to be accorded with a drug seeking or craving behaviour, as described by Murray [78 and 79], has often been overlooked. Moreover, this effect was no longer observed once it had been replaced with paracetamol [ 77 ].

Feinstein et al. Withdrawal is not likely to cause stimulation or sustainment of analgesic intake.