Relatively slow and long-lasting antimigraine effect of dihydroergotamine is most likely due to basic pharmacological attributes of the drug: A review

Abstract

Introduction

If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE’s antimigraine effect, which is the subject of this review, has only rarely been mentioned.

Methods

Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time.

Findings

Subcutaneous DHE 1 mg was inferior to subcutaneous sumatriptan 6 mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2 mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (T_max = 12 min).

Conclusion

DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE.

Keywords

Dihydroergotamine slow action long duration migraine

“Because of slow diffusion from the receptor biophase, the effects of [dihydroergotamine] DHE, as well as for ergotamine, last far longer than can be expected from plasma concentrations. For this reason, the pharmacokinetic data of ergotamine and DHE available cannot be used to predict the biologic response” (1).

Introduction

It is reasonable that a drug with slow dissociation from the receptor biophase will have a longer duration of action than a drug with a quick dissociation. It is less easy to understand that a slow dissociation will also result in a slower onset of action of the drug and a time lag between the drug response and blood concentrations of the drug (2). This time lag was suggested approximately 30 years ago (3,4) to be due to “a hypothetical compartment, the ‘effect compartment’, wherein the drug’s target was defined to reside” (2). The time needed for the drug to equilibrate between the plasma and effect compartment most likely results in the delayed response (2). This time lag has been demonstrated several times in pharmacokinetic/pharmacodynamic modelling in humans; for examples, see Sheiner et al.; Tfelt-Hansen and Paalzow; Tfelt Hansen; and Atkinson and Lalonde (3 –7). Possible reasons for the delay, other than simple slow dissociation from the receptor, have been described (2). An example of this dual phenomenon is the slow onset of action of intranasal dihydroergotamine (DHE) on dorsal hand veins (despite a quick absorption with a T_max of 30 min (8)) and a long lasting, constant effect for at least eight hours (h), as depicted in Figure 1 (8). The authors of the paper describing that study concluded in 1986 that the discrepancy could be due to a “deep effect compartment” (8). The dual vascular actions of parenteral ergot alkaloids have been known since 1985 for ergotamine (5) and 1986 for DHE (8).

Figure 1.

Change in hand vein diameter (%) at an occlusion pressure of 45 mm Hg and plasma concentrations of DHE (pg/ml) after intranasal DHE 1 mg (8). Note that whereas the plasma concentrations of DHE decrease from 0.5 hours (h) and further on, the effect on hand vein diameter increased up to two h and was then sustained up to eight h despite decreasing plasma concentrations of the drug (8). DHE: dihydroergotamine.

The long duration of action of DHE on migraines with fewer recurrences than triptans (9,10) has been well recognised (1,10). However, the slow onset of action of DHE for migraines (11,12) is not mentioned at all in recent papers on randomised, controlled trials (RCTs) with orally inhaled DHE (13,14) or in three recent reviews of DHE from 2012 (1,15,16). On the contrary, wider use of DHE was recommended in 2006 because of its, among other attributes, “rapid onset of action” (10). In 2010, intramuscular DHE was recommended for migraine attacks with very rapidly developing symptoms (17), and orally inhaled DHE was recently described as follows: “In a Phase 3 study, MAP0004 provided a rapid onset of pain relief and sustained effects at 24 and 48 hours after a single inhalation” (18).

It is uncertain whether the therapeutic effect of DHE on a migraine is exclusively due to constriction of extracerebral arteries (12) or whether there is also a central nervous system (CNS) effect with possible inhibition of the trigeminovascular system in the brain stem (12,19). The time-effect curves for DHE in vitro and in vivo evaluate mainly the vascular effect of DHE; thus, the final estimations of the time-effect curves for the initial effect of DHE in migraines can only be obtained from RCTs. In this review, we will discuss time-effect curves, in some cases up to four h after administration of DHE, for intravenous (20), subcutaneous (9,21), intranasal (22 –24) and orally inhaled DHE (13,14). In addition, some time-effect curves for DHE’s effect in vitro and in vivo will be briefly summarised and the pharmacokinetics of DHE will be described.

RCTs in which DHE was administered in different forms

Intravenous DHE

Intravenous DHE 0.75 mg was investigated in one small, placebo-controlled, crossover RCT (20) with a complicated design. Thirty-four migraine patients were first treated with the anti-emetic drug prochlorperazine 5 mg intravenously. After 30 minutes (min), the patients were randomised to either DHE (n = 19) or placebo (n = 15) intravenously. A possible effect was evaluated after 60 min and the patients were then crossed over to placebo or DHE and the effect was evaluated again after 90 min. Each time the patients rated their pain on a scale of 1 to 10. There was no difference between DHE (5.2) and placebo (4.7) at 60 min, and an advantage of intravenous DHE versus placebo could not be demonstrated (20). However, when comparing the sequence DHE plus placebo with the sequence placebo plus DHE at 90 min, the first sequence was superior (2.5) to the second (4.7). This could be due to a slow onset of action for intravenous DHE that was first apparent at 60 min after administration of the drug. However, the complicated design with intravenous prochlorperazine, an effective anti-migraine drug, (25,26) given 30 min before DHE and the small size of the RCT make interpretation very difficult.

Subcutaneous DHE

Subcutaneous DHE 1 mg has been compared with subcutaneous sumatriptan 6 mg in two RCTs (9,21). The comparative onset of anti-migraine effects, the maximum effects and the incidences of recurrence for subcutaneous DHE 1 mg and subcutaneous sumatriptan 6 mg were investigated in an RCT (n = 295) with migraine patients presenting with moderate or severe headache in clinics (9). Figure 2 shows the slower onset of headache relief (HR) for DHE compared with sumatriptan. After three h, the two drugs were comparable for HR (a decrease in headache from moderate or severe to none or mild) (9). Recurrence occurred in fewer patients with DHE (18%) than with sumatriptan (45%) (9). The authors concluded: “thus, the effect of dihydroergotamine on pain relief has a later onset but appears to be longer lasting than that of sumatriptan” (9). It should be noted that the discrepancy in the onset of effect cannot be due to general pharmacokinetic differences since the T_max is 10 min (12) and 20 min (27) for subcutaneous sumatriptan and subcutaneous DHE, respectively.

Figure 2.

Headache relief (HR) in a double-blind, randomised controlled trial (RCT) after subcutaneous DHE 1 mg or subcutaneous sumatriptan 6 mg in 295 migraine patients with moderate or severe (9). The slower increase in HR after DHE than after sumatriptan is apparent. After one h DHE (57%) was inferior to sumatriptan (78%) (p < 0.001); and after two h DHE (73%) was still inferior to sumatriptan (85%) (p = 0.002) whereas after three and four h the two drugs were equally effective (9). DHE: dihydroergotamine.

In one small double-blind RCT (n = 52), subcutaneous DHE 1 mg was compared with subcutaneous sumatriptan 6 mg, and HR was recorded every 10 min (21). After 30 min, sumatriptan (25/27 had HR) was superior to DHE (nine of 25 had HR) (p < 0.0001) but after 80 min there was no significant difference between sumatriptan (26/27 had HR) and DHE (21/25 had HR) (p = 0.18) (21). Apparently, subcutaneous sumatriptan acts quicker than subcutaneous DHE, but some of the difference could be due to a pharmacokinetic difference in T_max (12,27) between the two drugs, as described above. However, this is unlikely to be the whole explanation for the relative delay in the effect of DHE, and a slow action of DHE is probable but not proven because of the small size of the RCT (21).

Intranasal DHE

Intranasal DHE versus placebo

Up to 1992, intranasal DHE was compared with placebo in nine RCTs but most were published only in abstract form; thus, the results were difficult to judge (12,28). From 1994 to 1996, three papers (22 –24) on placebo-controlled RCTs of intranasal DHE appeared. All three RCTs (n = 503) with DHE 2 mg used a similar five-point scale for pain relief: from no relief to complete relief (22 –24) and results for pain relief over four h were combined, as shown in Figure 3. A slowly developing effect, measured by pain relief score, versus placebo was apparent. It should be noted that the T_max for intranasal DHE was estimated between 30 to 54 min (1,29). It is difficult to judge the clinical relevance of the differences in pain relief scores, but in one RCT (23) the HR at four h was greater for DHE (70%) than for placebo (28%) (p < 0.001) (23). At two h, the usual time point for evaluating acute migraine drugs, HR was achieved in 63% of the subjects receiving DHE and 24% receiving placebo (p < 0.001) (23).

Figure 3.

Combined analysis of three placebo-controlled RCTs (n = 503) with intranasal DHE 2 mg (22 –24). In all three RCTs a similar five-point scale for pain relief was used (22 –24). The mean therapeutic gains (active drug minus placebo) from one h to four h are shown and illustrate a slowly developing but modest increase in effect (increase in pain relief) with time. RCTs: randomised controlled trials; DHE: dihydroergotamine.

Intranasal DHE versus sumatriptan

Intranasal DHE 2 mg was compared with subcutaneous sumatriptan 6 mg in one cross-over RCT with 266 migraine patients (30). Sumatriptan was superior to DHE from 15 min to 120 min for HR and it was concluded by the authors: “that subcutaneous sumatriptan has a faster onset of action than DHE nasal spray and provides greater relief of acute migraine symptoms” (30). At two h, 80% of subjects receiving sumatriptan and 52% of subjects receiving DHE (30) had HR. When the final maximum effects are different for two drugs it is difficult to correctly estimate the speed of effect, as previously described (31). Similarly, in another cross-over RCT (n = 368) (32), intranasal sumatriptan 20 mg was superior to intranasal DHE 2 mg (headache relief at 60 min, the primary efficacy parameter, was 53% versus 41%, respectively; p < 0.001). A possible difference in the timing of the onset of effect could not be estimated because of the lack of similar maximum effects (31). In both cases (30,32), migraine patients are unlikely to worry about these theoretical considerations (31) and will likely prefer the drugs which work quickest.

Orally inhaled DHE

In one small phase II RCT (n = 63), orally inhaled DHE (MAP004) 0.5 mg apparently had a rapid onset of effect. DHE was superior to placebo at 10 min (therapeutic gain (TG) for HR: 31% (95% confidence interval (CI): 13–49%); 15 min (TG = 40% (95% CI: 17–63%)) and 30 min (TG = 41% (95% CI: 15–66%)) (Table 1) (13). This effect of DHE 0.5 mg was not present at 60 min (22% (95% CI: –9 to 52%)] but was present again at 90 min (TG = 32% (95% CI: 2–61%)) and two h (TG = 42% (13–70%)) and then not present at four h (TG = 28% (95% CI: –2 to 58%)) (Table 1). There was no HR for DHE 1 mg from 10 to 90 min, but after 120 min the TG was 35% (95% CI: 5–66%). This effect was gone by four h (TG = 20% (–12 to 52%)) (Table 1) (13).

Table 1.

Headache relief (a decrease in headache from moderate or severe to none or mild) at 10 minutes (min) to four hours (h) in a small phase II trial with MAP0004 (orally inhaled DHE) 0.5 mg and 1 mg and placebo (13).

Headache relief n/N (%)
Time after administration of DHE	MAP0004 0.5 mg (n = 26)	MAP0004 1 mg (n = 21)	Placebo (n = 16)	Therapeutic gain for MAP0004 0.5 mg (95% CI)	Therapeutic gain for MAP0004 1 mg (95% CI)
10 min	8/26 (32)	5/21 (22)	0/16 (0)	31% (13 to 49%)	24% (−6 to 42%)
15 min	12/26 (46)	5/21 (22)	1/16 (7)	40% (17 to 63%)	18% (−4 to 39%)
30 min	14/26 (55)	5/21 (24)	2/16 (14)	41% (15 to 66%)	11% (−13 to 36%)
60 min	17/26 (64)	11/21 (50)	7/16 (43)	22% (−9 to 52%)	9% (−24% to 41%)
90 min	18/26 (68)	13/21 (61)	6/16 (33)	32% (2 to 61%)	24% (−7 to 56%)
2 h	19/26 (72)	14/21 (65)	5/16 (33)	42% (13 to 70%)	35% (5 to 66%)
4 h	17/26 (65)	12/21 (55)	6/16 (40)	28% (−2 to 58%)	20% (−12 to 52%)

DHE: dihydroergotamine; CI: confidence interval.

In one large (n = 787) phase III placebo-controlled RCT with MAP0004 0.5 mg, the four primary endpoints “included the proportions of patients who achieved pain relief and those who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post treatment with no rescue medication use prior to the 2-hour time point” (14). For the four secondary endpoints, there were proportions of patients with pain relief at 10 min and four h (14). MAP0004 0.5 mg was superior to placebo for all four co-primary endpoints after two h (14). The TG (percentage with effect after active drug minus percentage with effect after placebo) at two h for HR was 24% (95% CI: 17–31%) and the TG for pain free at two h was 18% (95% CI: 13–24%); see Table 2 (14). The recurrence rate within 24 h (6%) was lower for MAP0004 than for placebo (15%) and the number of patients that were sustained pain free for two to 24 h was higher for MAP0004 (23%) than for placebo (7%) (14). At 10 min, MAP0004 was not superior to placebo but at 30 min a minor but significant effect (TG = 7%, 95% CI: 1–13%) was observed and the TG gradually increased at four h; see Table 2 and Figure 4. Adverse events occurred with similar incidences in 31% of MAP0004-treated patients and in placebo-treated patients (25%) (14). The plasma concentrations of DHE from a pharmacokinetic study in volunteers using MAP0004 0.5 mg (33) and the TG for headache relief in the large phase III RCT (14) are shown in Figure 4 and demonstrate a considerable time lag between response and plasma concentrations of DHE.

Figure 4.

Therapeutic gain (TG) for headache relief up to two hours (h) after orally inhaled DHE (MAP0004) 0.5 mg in a large phase III placebo-controlled, RCT (n = 787) (14). At 30 min a minor but significant effect (TG = 7%, 95% CI: 1–13%) was observed and the TG increased gradually for two h (14). In addition, plasma concentrations from a pharmacokinetic study in healthy volunteers are shown (33) in order to illustrate the time lag between headache relief and blood levels of DHE (Dr S. Kori from MAP Pharmaceuticals kindly provided the raw data for calculations of the mean plasma concentrations of DHE). DHE: dihydroergotamine; RCT: randomised controlled trial; CI: confidence interval.

Table 2.

Headache relief (a decrease in headache from moderate or severe to none or mild) and pain free at 10 minutes (min) to four hours (h) after 0.5 mg orally inhaled DHE (MAP0004) or placebo in a large phase III trial (14).

Time after administration of DHE	Headache relief, n/N (%)	Headache free, n/N(%)
Time after administration of DHE	MAP0004	Placebo	Therapeutic gain	MAP0004	Placebo	Therapeutic gain
10 min	33/388 (9)	22/387 (6)	3% (95% CI: −1 to + 6%)	4/369 (1)	2/370 (1)	1% (95% CI: −1 to + 2%)
30 min	111/385 (29)	83/385 (22)	7% (95% CI: 1 to 13%)	20/385 (5)	5/385 (1)	4% (95% CI: 1 to 6%)
60 min	187/391 (48)	110/391 (28)	20% (95% CI: 13 to 26%)	59/391 (15)	18/391 (5)	10% (95% CI: 6 to 15%)
2 h	232/395 (59)	137/397 (35)	24% (95% CI: 17 to 31%)	112/395 (28)	40/397 (10)	18% (95% CI: 13 to 24%)
4 h	254/393^a (65)	144/391^a (37)	28% (95% CI: 21 to 34%)	155/394 (39)	65/391 (17)	23% (95% CI: 17 to 29%)

DHE: dihydroergotamine; CI: confidence interval. ^aEscape medication was allowed after two h but there are no results for escape medication at two h given in the paper (Aurora et al. 2011) and the results at four h are thus uncertain.

Pharmacological investigations of time-effect curves of DHE

In vitro time-effect curves for DHE

In an in vitro preparation of canine saphenous veins, superperfusion with DHE (0.23 ng/ml) elicited an increase in tension, which had a slow onset and continued to increase even after the three h superperfusion ended (34). In a second series of experiments, canine femoral veins incubated for 10 min with DHE (2 × 10⁻⁷ M) elicited a slow, concentration-dependent increase in tension, which could not be eliminated by changing the bathing solution every 7.5 min for two h (Figure 5) (34). In an in vitro study using the middle cerebral artery of rats, DHE caused a slow onset of a contractile response with a time to maximum of 25–32 min (35). Repeated flushing of the bath caused a return to baseline 13–48 min after initiating the washing (35).

Figure 5.

The venostrictor effect of DHE (2 × 10⁻⁷ M) in vitro (in percentage to maximum noradrenaline-response) in a preparation of canine femoral vein (34). Ten minutes’ incubation with DHE elicited a slowly increasing constrictor effect, which could not be eliminated by changing the bathing solution every 7.5 minutes for two hours (34). DHE: dihydroergotamine.

In an in vitro preparation of human coronary arteries, the time required to reach peak contraction was longer for DHE and ergotamine than for triptans: DHE (18 ± 10 min), ergotamine (24 ± 13 min), sumatriptan (3 ± 2 min); zolmitriptan (4 ± 7 min) and rizatriptan (4 ± 2 min) (36). In the same preparation, the contractile response to DHE and ergotamine was sustained over a period of 90 min despite repeated washings every 15 min (36); whereas the response to triptans disappeared nearly completely after the second wash at 30 min (36).

In vivo time-effect curve of DHE in animals

In an in vivo study in cats, DHE inhibited central activation of the trigeminovascular pathway (19). About 30 min after the intravenous administration of a single, relevant dose of DHE, the probability of firing in cells at the C2 level of the cervical spinal cord (after superior sagittal sinus stimulation) was reduced, reaching a minimum at 45 min (19). The responses did not return to baseline in any animal after three h of observation (19).

Pharmacological investigations of DHE in humans

In one placebo-controlled study in human volunteers, subcutaneous DHE 0.5 mg caused a decrease in the diameter of the brachial artery one to 24 h after administration (27). The peak decrease (9.7%) was observed at 10 h (27). The T_max for DHE was 0.33 h and T_½ was six h (27). In another study in humans (8), intranasal DHE 1 mg resulted in a peak plasma concentration of DHE after 30 min that then declined with a half-life of three to four h; whereas the constrictor effect on hand veins developed slowly and reached a maximum (a decrease in diameter of 35 to 40%) after two to three h (8). This decrease then remained unchanged for eight h (8). The plasma concentrations of DHE and the effect on hand veins are shown for intranasal DHE 1 mg in Figure 1 (8).

Kinetics of DHE at the 5-HT1B/1D receptor

It was recently shown that DHE is tightly bound to the human 5-HT_1B/1D receptor in an in vitro assay comparing DHE and sumatriptan (37). The dissociation half-lives of DHE on 5-HT_1B (1.38 h) and 5-HT_1D (1.28 h) receptors were eight to 14 times longer than that of sumatriptan (5-HT_1B (0.17 h) and 5-HT_1D (0.09 h)) (37).

Pharmacokinetics of DHE

Some pharmacokinetics parameters for different administration forms of DHE are shown in Table 3 (1,27,29,33,38,39). It is remarkable that orally inhaled DHE (MAP0004) resulted in a shorter T_max (12 min) than both subcutaneous and intramuscular DHE (T_max: 20 to 40 min); see Table 3. After C_max, the loss of DHE curve in plasma followed a biphasic pattern (39). After subcutaneous DHE, the half-life for the α-phase was 1.4 h and the half-life for the β-phase was 22 h (39).

Table 3.

Some pharmacokinetic parameters for different administration forms of DHE.

Route of administration	Dose of DHE (mg)	T_max (min)	C_max (pg/ml)	Bioavailability (%)
Intravenous (33,38)	1	1–2	50.800	NR
Intramuscular (38)	1	24	3.000 pg/ml	ND
Subcutaneous (27,39)	1	20–40	3.480 pg/ml	ND
Intranasal (29)	2	30–54	1.000 pg/ml	40
Orally inhaled (33)	0.5	12	4.000 pg/ml	77

DHE: dihydroergotamine; NR: not relevant; ND: not determined.

Discussion

The pharmacological investigations of time-effect curves for the vascular effects of DHE showed a slow increase in the constriction induced by DHE over time both in vitro (34 –36), e.g. see Figure 5, and in vivo (8,27), e.g. see Figure 1. In one study (19), a DHE effect in the CNS first reached a maximum after 45 min but it remains uncertain whether this was due to slow penetration into the CNS or a delay in effect at the receptor site. The in vitro investigations are important because they demonstrate that the slowly developing effect of DHE is not dependent on active metabolites in humans, which are present especially after oral DHE administration (40) and much less so after parenteral administration of the drug (33). It is also unlikely that the slowly developing effect in humans is due to slow diffusion to a deep kinetic compartment. The slow vascular effect in vitro and the long duration of the effect (34,36) are most likely due to a slow dissociation of DHE from the human 5-HT_1B and 5-HT_1D receptors (37).

As mentioned in the Introduction, it is uncertain whether the anti-migraine effect of DHE depends on the constriction of extracerebral arteries (12) or a possible CNS effect (12,19), or both. Therefore, time-effect curves for the vascular effects of DHE cannot predict with certainty the effect of DHE on the treatment of migraine attacks. A total of eight RCTs evaluated the time-effect curves of DHE in acute migraine attacks, including: one with intravenous DHE (20), two with subcutaneous DHE (9,21), three with intranasal DHE (22 –24) and two with orally inhaled DHE (13,14).

The time-effect curve for the small placebo-controlled RCT with intravenous DHE (20) is very difficult to interpret because prochlorperazine was given as an antiemetic, although it was later shown to have antimigraine effects (25,26), 30 min before DHE or placebo. The other RCT with peculiar results is the small phase II trial with placebo, MAP004 0.5 mg and MAP0004 1 mg (13). An effect was found after 10 min with MAP0004 0.5 mg, but this was not consistent over time and, most important, this early effect could not be confirmed in the large phase III RCT (Table 2) (14). In addition, MAP0004 1 mg had no effect before 90 min (13).

The RCT comparing subcutaneous DHE 1 mg with subcutaneous sumatriptan 6 mg demonstrated that DHE is a slower acting drug for migraine than sumatriptan (Figure 2) (9). At three h, headache relief was quite similar for the two drugs (9). A much smaller RCT (21) also indicated that sumatriptan is a quicker acting drug than DHE. The three RCTs (22 –24) involving intranasal DHE 2 mg are summarised in Figure 3. A slowly increasing, modest effect over four h is illustrated in Figure 3. Analyses of HR, however, at two and four h in one RCT (23) indicated a clinically relevant effect of intranasal DHE 2 mg. In one phase III RCT (14), orally inhaled DHE 0.5 mg was superior to placebo from 30 min to four h (Table 2). The TG for the primary endpoint, HR at two h, was 24% (95% CI: 17–31%) (Table 2) and in a meta-analysis the TG for oral sumatriptan 100 mg was 31% (95% CI: 28–34%) (41). Despite a T_max for DHE concentration at 10 min, there was no apparent effect of DHE at this time point (Table 2). A considerable time lag between HR and plasma concentrations of DHE is illustrated in Figure 4. Such a time lag is typical for a drug with slow dissociation from the receptor (3 –6) and, as mentioned above, DHE has considerably longer dissociation half-lives from the human 5-HT_1B and 5-HT_1D receptors than sumatriptan (37). For subcutaneous DHE, intranasal DHE and orally inhaled DHE, the five RCTs (9,14,22 –24) all demonstrated a time-effect curve with a slow increase in efficacy of DHE over hours; see Figures 2, 3 and 4. In contrast, a positive consequence of the slow diffusion from the biophase is the long duration of action of DHE. This results in a low rate of recurrence after DHE (9,14). Similarly, a sustained vascular effect of DHE has also been observed in pharmacological investigations in human veins (1) and arteries (27). A similar effect-curve, slowly developing vascular effect and long duration of the effect have been observed for ergotamine (5). After intramuscular ergotamine 0.5 mg, the T_max was 30 min; whereas the time to maximum effect in leg arteries was six h (5). The vascular effect of ergotamine was pronounced after 30 h when no ergotamine could be measured in plasma (5). The likely consequence of this long duration of ergotamine is that the drug results in less recurrence than triptans (42).

In conclusion, DHE has basic pharmacology properties, a slow diffusion from the biophase (1) (most likely the result of a slow dissociation from the receptor (37)), which results in a time-effect curve for the anti-migraine effect of the drug with two characteristics: a slowly developing effect (Figures 2, 3 and 4) (9,14,22 –24) and a long duration of the effect resulting in relatively few recurrences (9,14). The possible clinical implications of this time-effect curve for the new orally inhaled formulation of DHE (MAP0004) will have to await comparisons with suitable formulations of triptans in RCTs.

Clinical implications

A slow dissociation of a drug from the receptor results generally in a long duration of action but also in a slow onset of action.

DHE has both a relatively slow onset and long duration of anti-migraine effect most likely to slow dissociation at the receptor biophase.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgement

During the process of writing the review several aspects of the time-effect curve for DHE were fruitfully discussed with Professor Paul Rolan, Adelaide, Australia.

Conflict of interest

None declared.

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