Abstract
Background
Microvascular decompression (MVD) is a surgical treatment for cranial nerve disorders via a small craniotomy. The postoperative pain of this procedure can be classified as surgical site somatic pain and postcraniotomy headache similar in nature to a migraine, including its association with photophobia, nausea, and vomiting. This headache can be difficult to treat and can impact on postoperative recovery. Sumatriptan is used to treat migraine-like headaches in various settings. This single-centre randomized controlled trial investigated whether postoperative administration of sumatriptan after MVD surgery impacts the quality of postoperative recovery.
Methods
Fifty patients who complained of postoperative headache after MVD were randomized to receive an s.c. injection of sumatriptan (6 mg) or saline. The primary outcome was quality of recovery as measured by the Quality of Recovery-40 (QoR-40) score at 24 h.
Results
The QoR-40 scores were significantly higher in the sumatriptan group (median 184; interquartile range 169–196) than in the placebo group (133; 119–155; P<0.01), suggesting higher quality of recovery. The sumatriptan group also had significantly lower headache scores at 4, 12, and 24 h. There were no significant differences in other secondary outcomes.
Conclusions
Use of sumatriptan improved the quality of recovery as measured by the QoR-40 and reduction of headache at 24 h after surgery. Sumatriptan is a useful alternative treatment for postcraniotomy headache. The mechanism remains unknown but could be related to reduction in headache, mood modulation, or both, mediated by a serotonin effect.
Clinical trial registration
Keywords: analgesia; headache; microvascular decompression surgery; recovery, postoperative; sumatriptan
Editor's key points.
Pain after craniotomy for microvascular decompression consists of both surgical site pain and migraine-like headache.
In a randomized controlled trial, the serotonin agonist sumatriptan led to improved quality of recovery scores and lower headache scores at 24 h after surgery.
Sumatriptan is a promising alternative treatment for postcraniotomy headache worthy of further investigation.
Microvascular decompression (MVD) is a surgical procedure used to treat cranial nerve disorders such as trigeminal neuralgia or hemifacial spasm.1,2 The current surgical approach uses a short suboccipital incision and a small craniotomy. After surgery, these patients experience significant pain that limits their recovery and originates from the surgical incision, in addition to a headache. The somatic incisional pain is usually short lived and responds well to conventional analgesia. Postcraniotomy headache is present in up to 65% of patients, but this can be higher after posterior fossa surgery.3 The headache is a complex type of pain reminiscent of a migraine headache and is associated with other unpleasant symptoms, such as photophobia, nausea, and vomiting. The mechanism is not fully understood but could involve meningeal irritation or loss of cerebrospinal fluid,4 which is difficult to avoid during minimally invasive craniotomy. This headache can affect the quality of recovery and has the potential for development of chronic pain.3,5–7 It is often difficult to treat because it does not respond well to conventional opioid analgesics.8 Furthermore, use of opioids can be associated with worsening of nausea and vomiting. Serotonin receptors are found in the brainstem near the trigeminal nuclei in the brainstem and in the vascular endothelium of meningeal vessels.9,10 Sumatriptan is a serotonin agonist that is useful for the treatment of migraine. It blunts the pain transmission through the trigeminovascular system and might be a useful analgesic for headache secondary to surgical pathology.11–13 The rapid onset of action of sumatriptan could potentially be useful for immediate postoperative management of headache, but it has not been tested for treatment of postcraniotomy headache.14–18
We hypothesized that sumatriptan is helpful in the management of headache and its associated symptoms after MVD, and that this is associated with improvement in the quality of recovery. We conducted a randomized controlled study to investigate the effects of s.c. administration of sumatriptan on postoperative headache and quality of recovery after MVD surgery.
Methods
This was a single-centre, randomized, double-blind controlled clinical trial that was registered at http://clinicaltrials.gov (NCT01632657). The institutional research ethics board approved the study protocol, and written informed consent was obtained from all participants. Adult patients (aged 18–80 yr) who underwent elective craniotomy for MVD of cranial nerves were invited to participate. Exclusion criteria were pregnancy, known sensitivity to sumatriptan or sulfonamide, history of ischaemic heart disease, uncontrolled hypertension, stroke, peripheral vascular disease, or severe hepatic impairment. Patients with a history of migraine and current or recent use of triptans or monoamine oxidase inhibitor drugs were also excluded.
I.V. induction of anaesthesia followed by tracheal intubation was performed. Anaesthesia was maintained with oxygen or air with sevoflurane and remifentanil infusion titrated to keep mean arterial pressure within 20% of baseline. Additional boluses of fentanyl 25–50 μg i.v. were used for intra-operative analgesia. Prophylactic antibiotics (cefazolin or clindamycin) and antiemetic (dexamethasone and ondansetron) were administered according to routine practice.
All operations were performed by a single neurosurgeon. The surgical site was infiltrated with 20 ml of bupivacaine 0.25% with 1:200 000 epinephrine before incision. No other forms of regional anaesthesia (e.g. scalp block) were performed. The same surgical technique was used for all patients. This involved a 5–6 cm skin incision over the junction of the sigmoid and transverse sinuses and a craniotomy ∼2.5 cm in diameter. At the end of the procedure, patients were transferred to the postanaesthetic care unit (PACU).
Subjects were randomized to receive an s.c. injection of either sumatriptan (6 mg) or placebo (0.9% saline) after MVD surgery, in the PACU. A computer-based, permuted block randomization method with a 1:1 allocation ratio and a variable block size was used. Sequentially numbered, opaque, sealed envelopes were used for allocation schedules and individual assignments. The subject and the investigator who assessed subjects after surgery were blinded to group allocation, as were the anaesthetist and the surgeon.
In the PACU, as soon as a subject complained of postcraniotomy headache, study drug was administered (0.5 ml of sumatriptan or placebo); only subjects who complained of headache in the PACU were randomized. There was no threshold for headache before randomization; all subjects who complained of postcraniotomy headache were included. Postcraniotomy headache was defined as having either pulsing or intense throbbing sensations in the fronto-temporal or occipito-nuchal regions, or both, accompanied by nausea, vomiting, or extreme sensitivity to light or sound. Subjects complaining of pain localized only to the surgical site and those with nausea and vomiting without headache were excluded. All other aspects of postanaesthetic care were routine. Subjects were asked to rate surgical site pain and headache severity at regular intervals using a numerical rating scale of 0–10; 0 was no pain and 10 was the worst pain imaginable. For surgical site pain, fentanyl 25 μg i.v. was administered every 5 min up to 200 μg to maintain a numerical rating scale score of <4. If needed, additional analgesia was provided with morphine 1–2 mg i.v. or hydromorphone 0.2–0.4 mg i.v. Postoperative nausea and vomiting (PONV) was treated with dimenhydrinate 25–50 mg i.v. or ondansetron 4 mg i.v., or both. Subjects were discharged from the PACU after 2 h to an inpatient surgical ward. Analgesia on the surgical ward consisted of either oral codeine 30 mg with acetaminophen 300 mg or oxycodone 5 mg with acetaminophen 325 mg. If oral medications were not tolerated, i.v. morphine or hydromorphone was used. Time to hospital discharge was recorded.
The Quality of Recovery-40 (QoR-40) questionnaire was administered 24 h after surgery. It consists of 40 questions that examine five domains of recovery using a five-point Likert scale.19 The five domains include physical comfort, pain, physical independence, emotions, and support. Other data collected included patient information, anaesthesia and surgical data, postoperative pain, sedation, PONV scores, and total analgesic consumption in the first 24 h.
The primary outcome was global QoR score at 24 h after surgery. Other outcome measures were pain and headache scores, total opioid consumption, and hospital discharge time. Global QoR-40 scores range from 40 to 200, representing very poor to outstanding. Mean (sd) QoR-40 scores at 24 h after major craniotomy have been reported to be 160 (19).20 No previous studies have evaluated QoR-40 scores after MVD. The median QoR-40 score at 24 h after short-stay and outpatient surgeries has been reported as 147, with interquartile range (IQR) 158–169.21,22 A 10-point difference represents an improvement in quality of recovery based on previously reported values of QoR-40 score after surgery and anaesthesia.23 In order to demonstrate a difference of 10 points in QoR-40, we calculated that 46 subjects would be required (23 treatment and 23 control) to detect a statistically significant difference between groups with α of 0.05 and power of 80%, assuming an sd of 12.
Data were tested for normality of distribution using the Kolmogorov–Smirnov test. Normally distributed continuous data are presented as the mean (sd) and were compared using Student's unpaired t-test. Ordinal data and non-normally distributed data are presented as the median (IQR). Data were compared between groups using the Mann–Whitney U-test. Categorical data were compared with χ2 test or Fisher's exact test where appropriate, with a value of P<0.05 used for all comparisons.
Results
A total of 50 subjects were recruited and randomized to receive sumatriptan (n=25) or placebo (n=25) for postoperative headache in the PACU (Fig. 1), all of whom were included for data analysis. Patient characteristics, symptom characteristics, and intra-operative management are shown in Table 1.
Fig 1.
CONSORT statement: flow diagram of study participants.
Table 1.
Subject characteristics. Data are shown as numbers (%) and mean (sd)
| Characteristic | Group 1 Sumatriptan (n=25) |
Group 2 Placebo (n=25) |
|---|---|---|
| Age [mean (range); yr] | 52.7 (35–69) | 50.1 (25–79) |
| Sex [male:female; n (%)] | 7 (28):18 (72) | 12 (48):13 (52) |
| BMI [mean (sd); kg m−2] | 28.4 (5.4) | 29.6 (6.8) |
| Co-morbidities [n (%)] | ||
| Cardiovascular | 7 (28) | 7 (28) |
| Respiratory | 4 (16) | 1 (4) |
| Gastrointestinal | 2 (8) | 5 (20) |
| Endocrine | 4 (16) | 5 (20) |
| Renal | 3 (12) | 4 (16) |
| Disease characteristics | ||
| Previous surgery [n (%)] | 7 (28) | 7 (28) |
| Disease duration [mean (sd); months] | 67.4 (51.3) | 45.2 (36.8) |
| Cranial nerve affected [n (%)] | ||
| V (trigeminal neuralgia) | 18 (72) | 23 (92) |
| VII (hemifacial spasm) | 7 (28) | 2 (8) |
| Side of surgery [n (%)] | ||
| Right | 14 (56) | 9 (36) |
| Left | 11 (44) | 16 (64) |
| Current treatment [n (%)] | ||
| Tricyclics | 1 (4) | 3 (12) |
| Gabapentinoids | 8 (32) | 8 (32) |
| Anticonvulsant | 7 (28) | 10 (40) |
| Multiple drugs | 8 (32) | 9 (36) |
| Intra-operative management | ||
| Fentanyl [mean (sd); µg] | 164 (96) | 173 (96) |
| Propofol [mean (sd); mg] | 250 (106) | 231 (88) |
| Rocuronium [mean (sd); mg] | 46 (19) | 47 (11) |
| Fluids given [mean (sd); ml] | 1070 (290) | 1160 (360) |
The QoR-40 scores are shown in Table 2, with median total scores for the sumatriptan and placebo groups of 189 (169–196) and 133 (119–155), respectively (P<0.01). Median scores for individual aspects of the QoR-40 (physical comfort, emotional state, physical independence, patient support, and pain) were all significantly higher in the sumatriptan group compared with the placebo group (Table 2).
Table 2.
QoR-40 scores in different dimensions. Values are the median (interquartile range). QoR-40, Quality of Recovery-40
| QoR-40 score dimension |
Group 1 Sumatriptan (n=25) |
Group 2 Placebo (n=25) |
P-value |
|---|---|---|---|
| Physical comfort | 54 (49–56) | 41 (32–47) | P<0.01 |
| Emotional state | 43 (39–45) | 31 (24–36) | P<0.01 |
| Physical independence | 23 (18–25) | 11 (10–20) | P<0.01 |
| Patient support | 35 (27–35) | 28 (22–33) | P<0.01 |
| Pain | 34 (28–35) | 25 (21–28) | P<0.01 |
| Total score | 184 (169–196) | 133 (119–155) | P<0.01 |
There were no significant differences in postoperative opioid consumption (morphine equivalants) between the groups. Median (IQR) opioid consumption for the sumatriptan and placebo groups, respectively, was 10 (7.5–19.5) and 10 (7.5–12.5) mg at 2 h, 10 (9.5–20) and 12.5 (10–14) mg at 6 h, 16 (10–22) and 14.5 (12.5–20) mg at 12 h, and 22.5 (10.5–26) and 20.5 (14–23) mg at 24 h. The median dose of acetaminophen used during 24 h was 1150 (IQR 0–1950) mg in the sumatriptan group and 975 (0–1650) mg in the placebo group (P=0.37).
Surgical site pain scores reported in the PACU are shown in Fig. 2. There was no statistically significant difference between the two groups. Headache scores in the two groups are shown in Fig. 3. Subjects in the sumatriptan group reported lower headache scores at 4, 12, and 24 h after surgery, and these differences were statistically significant.
Fig 2.
Surgical site pain scores as measured by the numerical rating scale. Pain score is shown at 5 (a), 30 (b), 60 (c), and 120 min (d). No statistical significance was detected by Student unpaired t-test.
Fig 3.
Headache scores over the first 24 h. Headache score is shown at 2 (a), 4 (b), 12 (c), and 24 h (d). The median headache scores are shown; *P < 0.05 by Student unpaired t-test.
The incidence of PONV throughout the postoperative period was 72% in the sumatriptan group and 60% in the placebo group (P=0.37). The two groups also had similar PONV scores that were not statistically different at any time point.
The median duration of hospital stay was 2 days (range 1–3 days) in both groups, with no statistical difference (P=0.7). There were no adverse events related to the use of sumatriptan.
Discussion
We found that subjects who received sumatriptan in the PACU reported lower headache scores and higher QoR-40 scores, indicating a higher quality of recovery. Overall, headache scores reported by all subjects were low, with a median score of 1–3 out of 10. Postoperative headache after MVD can be difficult to treat,7 and is often associated with unpleasant symptoms, such as nausea and vomiting, that delay recovery and hospital discharge. We did not show a reduction in hospital stay despite better QoR-40 scores because all subjects were discharged within 3 days.
The mechanisms for postcraniotomy headache are multifactorial and poorly understood. Factors such as traction on intracranial blood vessels, meningeal irritation, or loss of cerebrospinal fluid might play a role in activation of afferent C fibres on pial and dural blood vessels. Craniotomy leads to loss of cerebrospinal fluid and is necessary for better surgical access.4,24
Use of sumatriptan in this clinical setting has not been previously investigated, and our results present a novel alternative to the management of postcraniotomy headache. Sumatriptan has been used to treat migraine and atypical headaches associated with intracranial haemorrhage and aseptic meningitis.13–18,25 Postcraniotomy headache that is associated with nausea, vomiting, and photophobia can mimic migraine. Receptors for serotonin (5-hydroxytryptamine; 5-HT) are found in the central nervous system within the trigeminal nerve both near the dura and in the brainstem near the trigeminal nuclei. They are also located in neuronal tissue, vascular endothelium, and smooth muscle in meningeal blood vessels.9,10 Sumatriptan is a 5-HT receptor agonist that can act directly on the meningeal blood vessels or via inhibition of vasoactive peptides to cause vasoconstriction and attenuation of the process of nociception.11,12,26
We measured the QoR-40 rather than the pain score as the primary outcome. Pain relief is only one aspect of recovery, because other adverse symptoms can impact other aspects. The QoR-40 has been shown to have a high degree of reliability, acceptability, and feasibility.19,23,27 It is a multidimensional tool that measures aspects of recovery including pain, physical independence, physical comfort, emotional state, and psychological support and has been validated for neurosurgical patients, with a mean score reported to be 160.20
Surgical site pain scores were similar in the two groups measured at various time points in the PACU. Subjects in the sumatriptan group reported higher scores in the pain dimension of the QoR-40 and lower headache scores. This was not explained by differences in opioid usage, because the cumulative doses of opioid used were similar in the two groups.
Study limitations
Our study was adequately powered to demonstrate a difference in QoR-40 score, but other secondary measures, such as analgesic usage and pain scores, may still be subject to type II errors. Subjects who received sumatriptan also reported lower headache scores. Although this was statistically significant, the differences in headache score were 1–2 points on the severity scale, which might not be clinically significant.
Surgical site pain and postcraniotomy headache are difficult to differentiate, particularly in the immediate postoperative period, when they can be severe. We attempted to address this by explaining the difference between the two types of pain during the consent process and asking subjects to specify the site of pain in the PACU. Nonetheless, this is still a potential confounder in our study. Another potential limitation is the lack of pre-randomization headache scores that may have introduced bias. We did not specifically collect separate pre-randomization headache scores because we felt that subjects might not be able to differentiate the surgical site pain and headache accurately in the immediate postoperative period after posterior fossa craniotomy. However, surgical site pain scores at 5 min after arrival in the PACU were similar between groups.
We also did not differentiate the characteristics of the headache experienced. The triptan drugs are useful in the treatment of migraines and atypical headaches, including trigeminal neuralgia. It is possible that subjects differ in their perception of headache and pain, with a higher proportion of subjects experiencing headaches typical of migraine in the treatment group. These subjects could be more likely to benefit from sumatriptan. Sumatriptan has a rapid onset of action,28 which might explain the lower headache score observed as early as 4 h after surgery. The elimination half-life of sumatriptan is 2 h, and we used a low dose (6 mg) without repetition. It is therefore difficult to explain the sustained effects of a single dose of sumatriptan on QoR-40 throughout 24 h. The function of 5-HT as a neuromodulator is diverse, and it can modify affect and behaviour. Low 5-HT concentrations have been associated with suicide, and experimental studies to lower 5-HT concentrations have been shown to reverse the effects of antidepressants.29,30 As a 5-HT agonist, sumatriptan could play a role in mood modulation, thereby improving the emotional aspects of recovery as measured by the QoR-40.
We did not find any significant differences in opioid consumption between groups, but the study was not adequately powered to demonstrate significant differences in other postoperative parameters. This might also be attributed to the standard postoperative analgesic regimen used in our institution, where pain medications are administered by nursing staff on schedule. A study design with postoperative patient-controlled analgesia would be better suited to detect such differences. Our patient care pathway for MVD is well established, and we felt that it would not be appropriate to change this from our institutional standard. Likewise, patient discharge is also dictated by this pathway. Therefore, the duration of inpatient stay is unlikely to be affected by the QoR-40 and headache scores.
In conclusion, we showed that use of sumatriptan for postcraniotomy headache is associated with improved recovery as measured by the QoR-40 at 24 h after surgery. The precise mechanism for this remains unknown but could be related to reduction in headache scores or modulation of mood mediated by a 5-HT effect. Further research is required to investigate the role that sumatriptan plays in more extensive intracranial surgery and whether sumatriptan can have an extended effect on quality of recovery beyond 24 h.
Authors' contributions
Study design: L.V., T.B., M.T.
Study conduct: P.M., M.T.
Data analysis: L.V., L.L.
Writing the manuscript: L.V., L.L., T.B., P.M., M.T.
Declaration of interest
None declared.
Funding
Department of Anesthesia, Toronto Western Hospital, University of Toronto.
Acknowledgements
L.L. would like to acknowledge the travel grant from the Scottish Society of Anaesthetists for his fellowship. The authors thank Jigesh Mehta for his help with data collection.
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