The term migraine refers to a chronic neurological disorder characterized by persistent moderate to severe headaches that are usually linked to various autonomic nervous system symptoms. A typical case of migraine presents itself as a pulsating headache that affects only one side of the head for a period of two to seventy two hours. Within this period, the patient displays symptoms such as photophobia, vomiting, nausea and phonophobia. There are four documented sequential phases of a migraine i. e. the prodrome phase (1), aura phase (2), headache/ pain phase (3) and prodrome phase (4).
Analgesics such as nonsteroidal anti-inflammatory drugs are normally administered as first-line treatment in the control of migraines and agents such as triptans are prescribed as second-line treatment in cases where analgesics fail in effectiveness (5).
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NSAIDs also known as nonsteroidal anti-inflammatory analgesics or medicines (NSAIAs or NSAIMs) are analgesic and antipyretic drugs that have anti-inflammatory effects if used in high doses (6). These drugs are classified as mild analgesics and have a more substantial eﬀect on pain resulting from increased peripheral sensitization that occurs during inﬂammation that excites nociceptors to respond to stimuli that are painless in normal circumstances. Research carried out by Fitzgerald revealed that the inﬂammation practically leads to lowering of the response threshold of polymodal nociceptors (7).
There are two types of NSAIDs i. e. nonselective and selective depending on their ability to inhibit specific types of cyclooxygenase (COX) enzymes. COX -1 enzymes are normally found in the stomach, blood vessels and platelets whilst COX-2 enzymes are found at sites of inflammation. Non discriminating NSAIDs inhibit both COX-1 and COX-2 enzymes to a sizeable degree only for purposes of pain relief whilst selective NSAIDs (i. e. COX-2 inhibitors) are applicable in both pain relief and gastrointestinal protection. Selective NSAIDs are mostly preferred due to their dual protective effects especially for people with peptic ulcers (8).
Figure 1: Diagram showing the pharmacology of NSAIDs (www. levelofhealth. com)
The COX isoenzymes facilitate the formation of prostaglandins and thromboxane via the breakdown of arachidonic acid that stems from membrane phospholipids by the enzymatic action of phospholipase A2 (9). NSAIDs basically function by inhibiting the COX isoenzymes from converting arachidonic acid into the inflammation mediators thus resulting in relief from pain that is caused by inflammation.
Effects of NSAIDs on the pathophysiology of migraines
Activation of the trigeminovascular system (TGV) is an essential pain-generating
mechanism during a migraine attack. The COX isoenzymes facilitate the peripheral activation of the trigeminovascular system leading to the release of inflammatory substances that stimulate trigeminal first-order nociceptors to produce peripheral sensitization that correlates with the throbbing character of the head pain (10). NSAIDs are therefore effective in migraine therapy via action on the peripheral nociceptors (11).
The activation of second-order nociceptive neurons in trigeminal nucleus caudalis (TNC) is linked to the central sensitization which produces cutaneous allodynia of scalp and face during a migraine attack (12). PGE2 controls the activities of CGRP in the central terminals of the trigeminal sensory neurons (13) and enhances inflammatory stimuli (14). NSAIDs are effective in the cessation of the activation of second order trigeminal neurons and they attenuate allodynia induced by trigeminal ganglion compression (15). Migraine attacks are also associated with activation of brain stem areas (16); COX-1 is normally present in the periaqueductal grey matter whereas COX-2 can be found in LC and DRN (17), (18). COX inhibitors can potentiate opioid inhibition in the PAG (19), (20) and research has also shown that COX-1 in the PAG explains a focal component in the antinociceptive effects of NSAIDs (21),(22).
Pharmacology of triptans
Triptans (serotonin receptor agonists) are tryptamine based drugs that belong to the 5-
hydroxytryptamine 1B/1D (5-HT1B/1D ) class of drugs (23). They are used in the treatment of headaches, nausea, photosensitivity, vomiting and phonosensitivity associated with migraines in cases where NSAIDs fail in treatment (24). The pharmacological action of triptan is ascribed to the agonistic effects it has on serotonin 5-HT1B and 5-HT1D receptors in cranial blood vessels causing vasoconstriction and successive inhibition of pro-inflammatory neuropeptide release (25). Their effectiveness is further linked to the fact that they act on serotonin receptors in nerve endings as well as the blood vessels leading to decrease in the release of several peptides such as calcitonin gene related peptide (CGRP) and substance P.
Figure 2: Sumatriptan (triptan) binding to 5-HT 1D (www. en. wikipedia. org)
Effects of triptans in the pathophysiology of migraines
The vasoconstriction that result due to the effects of triptans on 5-HT1B in the smooth muscles lining the arteries mediate constriction of the blood vessels resulting in increase of blood flow velocity in the mid-cerebral vessels (26). Triptans are also thought to prevent the abnormal activation of peripheral nociceptors in the dura matter that triggers vascular changes including plasma protein extravasation (PPE) (27). In this case, triptans work by reducing PPE and preventing the peripheral release of vasoactive peptides, including substance P and (CGRP).
The strategic localization of 5-HT1D receptors on peptidergic nociceptors also indicates contribution of this receptor subtype in the reduction of peripheral activation by triptans (28). Research has shown that the microinjection of triptans into the periaqueductal gray selectively prevents durally-evoked nociceptive responses of TNC neurons with common dural and facial receptive fields (29).
Clinical evidence supporting the efficacy and safety of NSAIDs and triptans
A study carried out by Kivitz et al. (2002) on the efficacy of NSAIDs in the treatment of osteoarthritis and its accompanying symptoms such as headaches and migraines revealed that valdecoxib a COX 2 inhibitor is not only safe due to its gastro-protective nature but also very effective in treating mild to excessive pain caused by osteoarthritis and its symptoms. The study utilized a placebo-controlled, randomized, double-blind and multicenter study to determine the efficacy of the drug upon administration of three different dosages twice a day. The study involved patients who had been diagnosed with mild to severe arthritis. The study group was observed for 12 weeks to establish the safety of the drug by carrying out pre and post endoscopic analysis to examine ulcerations in addition to evaluating its efficacy. The results showed that Valdecoxib and placebos had the same ulceration effects thus indicating the safety of the NSAID. The study further revealed that administration of 20mg of Valdecoxib twice daily had an excellent effect on pain relief whilst administration of 5 and 10 mg yield much better results than placebos.
A publication by Goldstein et al. (2006) on the comparison between a combination of Acetaminophen, aspirin and caffeine versus ibuprofen (IB) in the treatment of acute migraine utilized a double-blind, multicenter, parallel-group, randomized, placebo-controlled, single-dose study to meet its objectives. 660 patients were recruited in the combination group, 666 in the ibuprofen group and 220 were given placebos. The results obtained indicated that despite the fact that the combination yielded better results in terms of pain intensity relief, headache response and freedom from pain. However the score difference was only 0. 3 indicating that if the combination was administered individually, then IB would be superior by a great margin. In terms of safety, the authors noted that IB is safe for use in addition to being cost effective.
A publication in the Cephalgia Journal volume 19 issue 4 published in 1999 (no listed authors) compared the efficacy and safety of diclofenac-potassium (NSAID) to oral sumatriptan and placebos in treatment of acute migraine attacks. The researchers pursued a double blind, placebo controlled and randomized crossover trial. The study enrolled 156 patients with or without aura in addition to symptoms such as photophobia and phonophobia. 50mg and 100mg of oral doses of diclofenac were compared to single dosages of 100mg sumatriptan. The results indicated that both dosages of diclofenac were more effective than placebo in migraine and symptoms management with effects realized within 60 minutes after dosing and the effects lasted up to 8 hours. Similarly, sumatriptan indicated the same results although the effects were only observed from the 90th minute. Diclofenac was not only effective and fast acting but also well tolerated and appeared to be superior to sumatriptan.
A publication by Touchon et al. (1996) compared the administration of subcutaneous sumatriptan to dihydroergotamine (DHE) nasal spray in the acute treatment of migraine. The research enrolled 266 migraineurs using a double-blind, multicenter, cross-over, double-dummy study design and data on efficacy and safety was collected periodically from the 15th minute after dosing. The results obtained showed that sumatriptan was notably superior to DHE in both migraine relief and migraine resolution. In terms of safety, both drugs were well tolerated given the adverse effects reported were not only mild but also transient.
A study conducted by Pfaffenrath et al. (1998) on the safety and efficacy of sumatriptan tablets concurred with the above findings. The design used in the study was a multinational, placebo controlled, double blind trial. A section of the patients enrolled were treated with 25mg, the second group was given 50mg and 100mg of the drug was administered in the third group. The results indicated that all doses were very effective when compared to the placebo and the effectiveness of the 25mg was realized 4 hours after administration whilst the higher doses only took 2 hours for the effects to be felt. In terms of safety, the adverse effects observed in the control group were similar to those observed in the treated group indicating that the triptan is also safe for use.
Kramer et al. (1998) published a paper to examine the efficacy and safety of rizatriptan. The study included 473 patients with migraines who were selected in a randomized manner, placebos were also included in the study. The research established that the drug was sustainably effective and well tolerated in migraine treatment. The antagonistic effects experienced were mild and dizziness was the most common, these effects were similar to those patients on placebos.
Critique of clinical evidence on the safety and efficacy of NSAIDs
A paper review published by Paradutz et al. (2010) on NSAIDs in the acute treatment of
migraine: a review of clinical and experimental data provides comprehensive data on the clinical evidence of efficacy and safety of NSAIDs highlighted above. The paper reviews and compares the efficacy and safety of different NSAIDs by carrying out placebo controlled double-blind randomized trials. The review resolved that there is colossal evidence that NSAIDs are effective in their actions against migraine attacks although there is a small percentage of scientific data on dose-response that indicate high effectiveness of NSAIDs upon administration of elevated doses.
The review also unveiled that there is no evidence indicating that one NSAID is more effective than another but recommended the selection of a drug with a rapid GI absorption and with the most favorable efficacy/side effect profile on the basis of the fact that COX-2 inhibitors cause less GI toxicity than nonselective NSAIDs although their therapeutic efficacy is not superior. In terms of safety, the review revealed that NSAID-induced side effects such as epigastric pain were minor in all trials. The age-adjusted relative risk of upper GI bleeding was on average 5. 3 across all NSAIDS.
The clinical trial design used in this study is very reputable thus worth emulating in future clinical trials. The approach involved incorporation of various clinical trials on NSAIDs and reviewed the efficacy and safety of these drugs in combination with either metoclopramide or caffeine. Most importantly, the design incorporated variations and eliminated bias by the inclusion of patients with both migraineurs with (MA) or without (MO) aura and exclusion of patients who did not present these symptoms. Generally the review was well articulated and the various aspects pertaining to the efficacy and safety of NSAIDs were well brought out indicating that the colossal research done on NSAIDs concur that the drugs are very effective with COX-2 inhibitors counteracting the undesirable GIT effects.
Critique of the clinical evidence on the efficacy and safety of triptans
A paper published by David et al. (2004) on the cardiovascular tolerability and safety of triptans: a review of clinical data clearly depicts the efficacy and safety of triptans. The data amassed from the collation of clinical trials revealed that triptans are sufficiently effective and greatly tolerated. The research also revealed that the cardiovascular complications associated with triptans are normally not serious.
The clinical design used in this review involved placebo controlled trials basing on the identification of sensations such as burning, tingling and chest tightness. These adverse effects associated with triptans evidently lacked in patients on placebo indicating that the negative effects were unique to the administration of triptans.
In essence, the inclusion and exclusion criterion used in this review was simple thus easily allowed for the identification of the side effects of triptans. The sample size selected in the determination of efficacy and safety of data was sufficient given the inclusion criteria of clinical evidence collated was based on; epidemiologic data on cardiovascular complications and migraine, clinical trials data on negative cardiovascular events, pharmacologic and pharmacodynamic studies relating to the cardiovascular safety of triptans, post marketing surveillance data on spontaneous reports of cardiovascular adverse scenarios with triptans and methods of evidence-based clinical assessment of cardiovascular risk. This permitted the reviewers to have ample data that facilitated critical analysis of the triptans effects.
In general, the paper is very comprehensive and presents no limitations. It is evident that the incidence of triptan-associated cardiovascular events in both clinical trials and clinical practice were extremely low as earlier indicated. The review further indicated that nonischemic mechanisms are responsible for triptan-related chest symptoms in patients not affected by coronary artery disease. The conclusions of this review cannot therefore be extended to patients suffering from cardiovascular disease. The cardiovascular safety profile of triptans favors their use in those without cardiovascular disease and those with a low suspicion of cardiovascular disease only.
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