The problem
There is increasing evidence that people who have undergone brain surgery experience significant pain. This pain can have serious consequences including raised blood pressure, agitation, prolonged recovery time and an increased risk of long-term headaches. Research studies have looked at different drugs in an attempt to reduce the risk of pain for these people. There is now more evidence about pain reduction options for adults undergoing brain surgery but there remains uncertainty as to which options work best.
The question
This review aimed to determine which drugs provide the best chance of reducing pain for adults undergoing brain surgery, by collecting and combining the results of studies that looked at pain-relieving drugs for this patient group. To provide an accurate answer to this question, only studies conducted in accordance with an approved high standard were included. Studies published in different languages and countries were included in order to obtain as much information as possible.
In addition to determining which drugs were best at preventing or reducing pain after brain surgery, this review attempted to determine additional information such as how much additional pain-relieving treatment was required in addition to the treatment under study; whether participants' pain was adequately controlled or not; how drowsy the participants were; what side effects they experienced; and how long they needed to stay in intensive care and in hospital. This review also considered whether some treatments worked better when given before or after surgery or for people undergoing different approaches to brain surgery.
The results
A total of 43 eligible studies, (42 complete and one still in progress), were found. Of the 42 completed studies (3548 participants), 10 studied injections of local anaesthetic into the scalp, 12 studied injection of local anaesthetic around specific scalp nerves, 8 studied nonsteroidal anti-inflammatory drugs (NSAIDs), 4 studied dexmedetomidine, 4 studied acetaminophen aka paracetamol), 2 studied opioid drugs, 3 studied gabapentin or pregabalin (anti-seizure drugs that can also be used for pain relief) together with 1 study each of local anaesthetic injected into the veins, local anaesthetic injected into the jaw and the drug flupirtine.
Sufficient information was abstracted to calculate the overall pain-preventing effects of the following: local anaesthetic injections around the surgical wound, local anaesthetic injections around specific scalp nerves, NSAIDs, acetaminophen, dexmedetomidine and pregabalin or gabapentin. When only high-quality studies were examined: NSAIDs reduced pain up to 24 hours after surgery, dexmedetomidine and local anaesthetics injected around specific scalp nerves reduced pain in the first 12 hours after surgery, pregabalin or gabapentin reduced pain in the first 6 hours after surgery and local anaesthetic injections around the surgical wound significantly reduced pain 48 hours after surgery, but did not affect pain at earlier time points.
When the timing of injection of local anaesthetics was examined, local anaesthetics injected around specific scalp nerves provided better early pain relief (first 6 hours) when injected after surgery and better late pain relief (12 and 24 hours) when injected before surgery.
The following interventions were also found to reduce the need for additional pain-relieving drugs: local anaesthetics injected around specific scalp nerves and dexmedetomidine. Gabapentin or pregabalin was found to reduce the risk of nausea and vomiting after surgery.
Acetaminophen was not found to prevent pain after brain surgery or reduce the need for additional pain-relieving drugs.
Insufficient evidence was found to determine whether any of these drugs made the participants more or less drowsy, affected how long they needed to stay in intensive care or whether different drugs worked better for adults undergoing different approaches to brain surgery.
The overall quality of the evidence that contributed to the results of this review was assessed and judged to be 'high' for pain-reducing effects of NSAIDs, 'moderate' to 'low' for pain-reducing effects of dexmedetomidine, acetaminophen, pregabalin and gabapentin and local anaesthetics injected around specific scalp nerves and ' low' to ' very low' for pain-reducing effects of local anaesthetic injections around the surgical wound, additional pain relief requirements and risk of nausea and vomiting after surgery .
There is high-quality evidence that NSAIDs reduce pain up to 24 hours postoperatively. The evidence for reductions in pain with dexmedetomidine, pregabalin or gabapentin, scalp blocks, and scalp infiltration is less certain and of very low to moderate quality. There is low-quality evidence that scalp blocks and dexmedetomidine may reduce additional analgesics requirements. There is low-quality evidence that gabapentin or pregabalin may decrease nausea and vomiting, with the caveat that the total number of events for this comparison was low.
Pain following brain surgery can compromise recovery. Several pharmacological interventions have been used to prevent pain after craniotomy; however, there is currently a lack of evidence regarding which interventions are most effective.
The objectives are to assess the effectiveness of pharmacological interventions for prevention of acute postoperative pain in adults undergoing brain surgery; compare them in terms of additional analgesic requirements, incidence of chronic headache, sedative effects, length of hospital stay and adverse events; and determine whether these characteristics are different for certain subgroups.
We searched MEDLINE, Embase, CINAHL, CENTRAL, Web of Science and two trial registries together with reference checking and citation searching on 28th of November 2018.
We included blinded and non-blinded, randomized controlled trials evaluating pharmacological interventions for the prevention of acute postoperative pain in adults undergoing neurosurgery, which had at least one validated pain score outcome measure.
We used standard Cochrane methodological procedures. We calculated mean differences for the primary outcome of pain intensity; any pain scores reported on a 0 to 100 scale were converted to a 0 to 10 scale.
We included 42 completed studies (3548 participants) and identified one ongoing study.
Nonsteroidal anti-inflammatories (NSAIDs)
Nonsteroidal anti-inflammatories (NSAIDs) reduce pain up to 24 hours (0 to 6 hours, MD −1.16, 95% CI −1.57 to −0.76; 12 hours, MD −0.62, 95% CI −1.11 to −0.14; 24 hours, MD −0.66, 95% CI −1.18 to −0.13; 6 studies, 742 participants; all high-quality evidence). Results for other outcomes were imprecise (additional analgesic requirements: MD 1.29 mg, 95% CI −5.0 to 2.46, 4 studies, 265 participants; nausea and vomiting RR 1.34, 95% CI 0.30 to 5.94, 2 studies, 345 participants; both low-quality evidence).
Dexmedetomidine reduces pain up to 12 hours (0 to 6 hours, MD −0.89, 95% CI −1.27 to −0.51, moderate-quality evidence; 12 hours, MD −0.81, 95% CI −1.21 to −0.42, low-quality evidence). It did not show efficacy at 24 hours (MD −0.08, 95% CI −0.32 to 0.16; 2 studies, 128 participants; low-quality evidence). Dexmedetomidine may decrease additional analgesic requirements (MD −21.36 mg, 95% CI −34.63 to −8.1 mg, 2 studies, 128 participants, low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting RR −0.43, 95% CI 0.06 to 3.08, 3 studies, 261 participants; hypotension RR 0.5, 95% CI 0.05 to 5.28, 3 studies, 184 participants; both low-quality evidence).
Scalp blocks may reduce pain up to 48 hours (0 to 6 hours, MD −0.98, 95% CI −1.66 to −0.3, 10 studies, 414 participants; 12 hours, MD −0.95, 95% CI −1.53 to −0.37, 8 studies, 294 participants; 24 hours, MD −0.78, 95% CI −1.52 to −0.05, 9 studies, 433 participants, all low-quality evidence; 48 hours, MD −1.34, 95% CI −2.57 to −0.11, 4 studies, 135 participants, very low-quality evidence. When studies with high risk of bias were excluded, significance remained at 12 hours only. Scalp blocks may decrease additional analgesia requirements (SMD −1.11, 95% CI −1.97 to −0.25, 7 studies, 314 participants). Results for other outcomes were imprecise (nausea and vomiting RR 0.66, 95% CI 0.33 to 1.32, 4 studies, 165 participants, very low-quality evidence).
Scalp Infiltration may reduce pain postoperatively but efficacy was inconsistent, with a significant effect at 12 and 48 hours only (12 hours, MD −0.71, 95% CI −1.34 to −0.08, 7 studies, 309 participants, low-quality evidence; 48 hours, MD - 1.09, 95% CI -2.13 to - 0.06, 3 studies, 128 participants, moderate-quality evidence). No benefit was observed at other times (0 to 6 hours, MD −0.64, 95% CI −1.28 to −0.00, 9 studies, 475 participants, moderate-quality evidence; 24 hours, MD −0.39, 95% CI −1.06 to 0.27,6 studies, 260 participants, low-quality evidence. Scalp infiltration may reduce additional analgesia requirements MD −9.56 mg, 95% CI −15.64 to −3.49, 6 studies, 345 participants, very low-quality evidence). When studies with high risk of bias were excluded, scalp infiltration lost the pain benefit at 12 hours and effects on additional analgesia requirements, but retained the pain-reducing benefit at 48 hours (MD −0.56, 95% CI −1.20 to -0.32, 2 studies, 100 participants, very low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting, RR 0.74, 95% CI 0.48 to 1.41, 4 studies, 318 participants, low-quality evidence).
Pregabalin or gabapentin may reduce pain up to 6 hours (2 studies, 202 participants), MD -1.15,95% CI −1.66 to −0.6, 2 studies, 202 participants, low-quality evidence). One study examined analgesic efficacy at 12 hours showing significant benefit. No analgesia efficacy was shown at later times (24 hours, MD -0.29, 95% CI -0.78 to -0.19; 48 hours, MD - 0.06, 95% CI -0.86 to 0.77, 2 studies, 202 participants, low-quality evidence). Additional analgesia requirements were not significantly less (MD −0.37 (95% CI −1.10 to 0.35, 3 studies, 234 participants, low-quality evidence). Risk of nausea and vomiting was significantly reduced (RR 0.51, 95% CI 0.29 to 0.89, 3 studies, 273 participants, low-quality evidence). Results for other outcomes were imprecise (additional analgesia requirements: MD −0.37, 95% CI −1.10 to 0.35, 3 studies, 234 participants, low-quality evidence).
Acetaminophen did not show analgesic benefit (0 to 6 hours, MD −0.35, 95% CI −1.00 to 0.30; 12 hours, MD −0.51, 95% CI −1.04 to 0.03, 3 studies, 332 participants, moderate-quality evidence; 24 hours, MD -0.34, 95% CI -1.20 to 0.52, 4 studies, 439 participants, high-quality evidence). Results for other outcomes remained imprecise (additional analgesia requirements, MD 0.07, 95% CI −0.86 to 0.99, 4 studies, 459 participants, high-quality evidence; length of hospitalizations, MD −3.71, 95% CI −14.12 to 6.7, 2 studies, 335 participants, moderate-quality evidence).