Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

Abstract

BackgroundPain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.DiscussionIn this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.SummaryMultitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.

Textbook of Personalized Medicine

“…Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and enable personalization of treatment to the patient's specifi c needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies (Straube et al 2011 ).…”

Novel analgesic combination of tramadol, paracetamol, caffeine and taurine in the management of moderate to moderately severe acute low back pain

“…5 Also caffeine has been found to accentuate the analgesic effects of acetaminophen and acetyl salicylic acid (ASA) in a broad collection of pain states such as dysmenorrhoea, cancer pain, post-partum pain, sore throat and dental post-surgery pain. 6 Taurine a conditionally essential amino acid containing sulphur is found in almost all tissues in mammals. 7 Taurine plays vital roles in a large number of physiological and pathological conditions in human body, such as the cytoprotective functions, antioxidant, anti-inflammatory and anti-apoptosis effects.…”

Pharmacological Synergy, Multi‐Target Therapeutics – The Past and the Future in Headache Therapy?

“…Another therapeutic benefit of combinations not mentioned by Blumenfeld et al could be that only the combination triggers mechanisms that have not been found in the pharmacological profile of the single substances as such 2 . The combination with caffeine increases, by contrast, the potency of the ASA + acetaminophen combination 3 .…”

“…As is well known, this is not the case. On the contrary, in the pre‐triptan era headache therapy, and in particular, migraine treatment, was characterized by the predominant use of combinations of various medications – both in prescription drugs and over‐the‐counter medications, which we showed in our recently published review “Combined Analgesics in (Headache) Pain Therapy: Shotgun Approach or Precise Multi‐target Therapeutics?.” 2 A classical example is the combination with caffeine, which has shown superior efficacy (eg, the combination of acetylsalicylic acid [ASA] + acetaminophen+caffeine vs the combination without caffeine, the single analgesics and placebo 3 ). On the other hand, the pharmacokinetic profile of ASA is improved by acetaminophen 4 in combination with sumatriptan and naproxen (example given by Blumenfeld et al).…”

“…The crux of the matter is to decide what is expected, and various rules have been proposed to this end (for example, that the expected effect is the sum of the effects of the individual constituents of the combination, or that it is the product of these effects), notes Berenbaum 8 . However, in pain and headache therapy, the largest class of non‐opioids, the non‐steroidal anti‐inflammatory drugs (NSAIDs), show often a surprisingly flat dose response, 9 a maximal dose, or marked ceiling (plateau) effects 2 . Higher NSAID doses provide no additional analgesia 10 …”