Patients undergoing craniotomy surgery have traditionally been thought to experience minimal pain and discomfort postoperatively. Standard neurosurgical and anaesthetic textbooks either do not mention post-craniotomy pain [1-3] or suggest that it is not a significant problem [4-6]. These assumptions are based on a 1977 study by Geevarghese in which it is stated that there is no postoperative pain as movement does not increase tension in tissues of the operative site .
This conventional ideology that post-craniotomy patients have reduced analgesic requirements has recently been challenged [8,9]. Studies have shown that patients undergoing craniotomy surgery experience varying degrees of pain postoperatively from mild discomfort to severe pain [10,11]. A variety of terms have been used by patients to describe this pain such as pulsating and pounding, tensive, continuous and steady, heavy, stabbing or burning . Almost 9 out of 10 neuroanaesthetists, surveyed in one study, use the weak opioid codeine phosphate as first-line analgesic postoperatively . Yet over half of them considered that in up to 50% of patients it provided inadequate relief. Despite this, intramuscular (i.m.) codeine phosphate remains the main analgesic used in the postoperative period and has been for the past 30 yr [7,9].
At the regional neurosurgical unit in the University Hospital of Wales, Cardiff, it has become evident that many patients undergoing craniotomy surgery experience moderate to severe pain after surgery. In today's healthcare setting where evidence based medicine and clinical effectiveness are of paramount importance it was felt that benchmarking with other units across the UK was imperative in order for an evidence based standard to be established.
A postal questionnaire (Box 1) was sent to the Senior Nurse of every Neurosurgical Directorate within the UK (as defined by the Directory of Critical Care Units, UK 2003) . Due to the poor response rate from neuroanaesthetists in previous studies  it was felt that targeting the senior nurse on each unit would provide a more comprehensive picture of post-craniotomy practices.
The senior nurse was asked what the first-line analgesic for post-craniotomy patients was in the immediate postoperative period (first 48 h after surgery). In addition, the route by which they were administered and prescription of supplementary analgesia were also sought. Furthermore, it was queried whether formal pain assessment tools were used to assess pain regularly and which healthcare professional undertook such an assessment. Nurses were also queried as to whether any centre used a specific pain assessment tool for cognitively impaired patients (e.g. patients who were dysphasic/aphasic).
Of the 33 centres that were sent questionnaires, 21 were initially returned. Units that had not responded within 1 month of the questionnaires being sent were telephoned and prompted to return their responses. A further three questionnaires were subsequently returned resulting in a response rate of 73%. One questionnaire was inappropriately completed (two questions were left unanswered) and so was therefore withdrawn. The remaining 23 (70%) were used in the data analysis.
In 78% of centres codeine phosphate was the principal analgesic used post-craniotomy with only 13% of centres using morphine and 9% using dihydrocodeine. Of the 18 units, which used codeine, 14 (78%) used a combination of either the oral or i.m. route depending on the patient's ability to tolerate diet and fluids. Four units (22%) stated that codeine phosphate, in the immediate postoperative period, was only given i.m. Of the units, which routinely used morphine as their first-line analgesic, one used i.m., one subcutaneous and one intravenously (i.v.) via a patient-controlled analgesic (PCA) device. One further unit mentioned that they were about to start clinical trials on the use of morphine PCA for post-craniotomy patients. Furthermore, four units stated that they occasionally used tramadol depending on the neuroanaesthetist's preference.
Only 52% of the units routinely prescribed analgesia regularly, with 48% prescribing analgesia as required. The majority of units (82%) used supplementary analgesia for its synergistic effects with only four neurosurgical centres solely prescribing opioids postoperatively (Fig. 1). Paracetamol was used by all of the units prescribing balanced analgesia: 30% (7 units) stated that in addition to paracetamol they also routinely used diclofenac. One unit occasionally used diclofenac although it was not routine practice and one only prescribed diclofenac after the first 24 h post-surgery.
Documented assessment of pain, using a formalized and verified assessment tool only occurred in 57% of centres with 10 units stating that they did not undertake pain assessment routinely in post-craniotomy patients. The majority of the units that undertook pain assessment regularly used the verbal categorical scale (85%) whilst the remainder used the visual analogue scale (VAS) (15%). In most instances, it was the ward nurse who undertook regular pain assessments and documented these in the patient's notes (92%); however, one unit stated that pain assessments were routinely carried out by both the ward nurse and the ward doctor. None of the units surveyed acknowledged that an anaesthetist routinely undertook regular and sustained pain assessments. Three units stated that for patients with dysphasia or aphasia face recognition pain assessment tools were used. However, none of the units used a verified pain assessment tool specifically for the cognitively impaired.
This study demonstrates that codeine phosphate continues to be the first-line analgesic used post-craniotomy in the majority of neurosurgical centres in the UK. Codeine is considered to be a weak opioid  that is believed to mediate its analgesic effect predominantly through agonist activity at mu receptors . The major metabolic pathway of codeine is the formation of codeine-6-glucuronide . Thus the O-demethylation of codeine to morphine constitutes only a minor pathway accounting for approximately 5-15% of the dose administered [17-19].
The efficacy of codeine is further confounded by large interindividual and interethnic differences in demethylation capacity [20-22]. The enzyme that catalyses the demethylation of codeine to morphine, cytochrome P-450 CYP2D6, exhibits a genetic polymorphism with over 50 known different genetic variants resulting in up to 15% of caucasians experiencing no analgesic effect from codeine [23-25].
In addition, this survey has demonstrated that codeine is often delivered via the i.m. route. However, many authors have questioned the ethics of patients receiving i.m. injections when they have an i.v. line [26,27]. Intramuscular injections can lead to variable pain control due to inadequate, fluctuating and unpredictable blood concentrations as well as being painful to the patient . Repeated i.m. injections of analgesics have been associated with fever as a result of tissue injury secondary to drug administration or hypersensitivity . Two studies looked at the efficacy of i.m. codeine on post-craniotomy pain [10,30] and demonstrated inadequate pain relief following i.m. codeine administration.
In this survey, several neurosurgical centres stated that they occasionally used tramadol. Many adverse events have been noted following tramadol administration, in particular significantly higher nausea and vomiting scores than either morphine [31,32], codeine [33,34] or placebo . This is a significant concern as vomiting can result in a sharp increase in intracranial pressure , potentially increasing the risk of intracerebral haematoma and neurological dysfunction . Furthermore, tramadol carries a risk of enhanced seizure activity in patients taking seizure threshold reducing drugs and those with epilepsy or other seizure risk. Although the risk appears to be small (approximately 1% of the population taking tramadol) [38,39], further research is needed to verify the incidence of tramadol-associated seizures following craniotomy.
Only three of the units surveyed stated that they routinely used morphine post-craniotomy, one of which used PCA. Intravenous morphine provides more effective analgesia postoperatively than either codeine [8,10,22,24,35] or tramadol [31,32] and is held up as a golden standard against which all other opiates are judged. Yet whilst morphine is often the drug of choice in most postoperative settings, this survey demonstrates that its use continues to be limited post-craniotomy.
One of the concerns of using morphine post-craniotomy is opioid-induced respiratory depression . The resulting retention of carbon dioxide can lead to an increase in cerebral blood flow and raised intracranial pressure in patients whose intracranial compliance is compromised . Only one study has demonstrated an increase in partial pressure of CO2 in arterial blood (PaCO2) following incremented doses of morphine post-craniotomy . It was suggested that small doses of morphine might cause ‘luxury perfusion’ and impair cerebral circulation although this phenomenon was only noted in 3 of the 30 patients studied and there was no deterioration in neurological or vital signs. These results are similar to another study, which noted that PaCO2 rose significantly following morphine administration (0.143 mg kg−1) when compared to tramadol administration (0.5-2.0 mg kg−1) (P < 0.01) in abdominal surgery . No adverse events were noted.
Goldsack and colleagues found no differences in PaCO2, respiratory rate, heart rate or arterial blood pressure in 40 subjects receiving morphine or codeine , neither drug causing significant variation from the baseline values. This coincides with the findings of Pasero and McCaffery who demonstrated that the incidence of clinically significant respiratory depression following morphine in hospitalised adults was less than 1% . All equipotent opioids have the potential to cause respiratory depression . There have been no studies of the effects of morphine or other narcotics on PaCO2 of patients with borderline or raised intracranial pressure.
Pain can only be treated effectively if it is assessed appropriately and regularly using valid and rigorous assessment tools . Pain assessment is therefore seen as pivotal to achieving effective pain management. This study demonstrated that only 57% of units surveyed undertook routine pain assessment using a formalized pain assessment tool. None of the units used a validated pain assessment tool specifically for the cognitively impaired. There is no pain assessment tool specifically for dysphasic patients although numerous studies have demonstrated the effective use of pain assessment tools for cognitively impaired children [44,45]. Objective, valid and rigorous pain assessment tools are required to facilitate effective pain management in this vulnerable population.
Almost 10 yr after Stoneham and Walters' study , post-craniotomy analgesic practices do not appear to have progressed or developed. Codeine phosphate continues to be the first-line analgesic used in the majority of neurosurgical centres in the UK. However, the significant variability in its demethylation and uncertainties regarding its efficacy and any possible advantages over morphine or tramadol mean that its use cannot be recommended without reservation. Post-craniotomy pain is known to be significant and pain assessment problematic. Thus the difficulties in treating post-craniotomy pain may only be heightened by the use of codeine and inappropriate assessment tools. There is a need for properly structured and methodologically robust studies to investigate the efficacy, safety and appropriateness of morphine PCA in post-craniotomy patients and valid pain assessment tools need to be developed specifically for cognitively impaired adults.
1. Aitkenhead A, Smith G, eds. Neurosurgical Anaesthesia
, 3rd edn. New York, USA: Churchill Livingstone Inc, 1998.
2. Craft T, Upton P. Key Topics in Anaesthetia
, 2nd edn. Oxford, England: BIOS Scientific Publishers Ltd, 1997.
3. Drummond J, Patel P. Neurosurgical Anaesthesia. In: Miller R, ed. Anaesthesia
, 5th edn, Vol. 2. New York, USA: Churchill Livingstone Inc, 2000.
4. Atkinson R, Rushman G, Davies N. Lees Synopsis of Anaesthesia
, 11th edn. Oxford, England: Butterworth Heinnemann Ltd, 1993.
5. Feldman S. Neurological conditions and anaesthesia. In: Churchill Davidson H, ed. A Practice of Anaesthesia
, 5th edn. London, England: Lloyd Luke (Medical Books) Ltd, 1984.
6. Turner J. Anaesthesia for neurosurgery. In: Healey T, Cohen P, eds. A Practice of Anaesthesia
, 6th edn. London, England: Edward Arnold, 1995.
7. Geevarghese K. Post operative care of the patient undergoing neurological surgery. Int Anaesthesiol Clin
8. Stoneham M, Cooper R, Quiney N, Walters F. Pain
following a craniotomy
: a preliminary study comparing PCA morphine
with intramuscular codeine
9. Stoneham M, Walters F. Post operative analgesia
patients: current attitudes among neuroanaesthetists. Eur J Anaesthesiol
10. Goldsack C, Souplak S, Smith M. A double blind comparison of codeine
for post operative analgesia
following intracranial surgery. Anaesthesia
11. Graham A, Reid M, Andrews P. Perception of pain
experienced and adequacy of analgesia
following elective craniotomy
12. De Benedittis G, Lorenzetti A, Miglione M, et al
. Post-operative pain
in neurosurgery: a pilot study in brain surgery. Neurosurgery
13. Directory of Critical Care. Directory of Critical Care UK
. London, England: CMA Medical Data, 2003.
14. Cousins M, Umedaly H. Post-operative pain
management in the neurosurgical patient. Int Anaesthesiol Clin
15. Way W, Fields H, Schumacher M. Opioid analgesics
and antagonists. In: Katzung B, ed. Basic and Clinical Pharmacology
, 8th edn. New York, USA: Langer Medical Books, 2001.
16. Dollery C. Therapeutic Drugs
, Vol. 1. Edinburgh, Scotland: Churchill Livingstone Inc, 1991.
17. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine
after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol
18. Desmules J, Gascon M, Dayer P, et al
. Impact of environmental and genetic factors on codeine analgesia
. Eur J Clin Pharmacol
19. Yue Q, Hasselstrom J, Svensson J, et al
. Pharmokinetics of codeine
and its metabolites in Caucasian healthy volunteers. Br J Clin Pharmacol
20. Quilding H, Lundqvist G, Boreus L, et al
. Analgesic effect and concentration of codeine
after 2 dose levels of codeine
following oral surgery. Eur J Clin Pharmacol
21. Sindrup S, Brosen K, Bjerring P, et al
thresholds to copper vapour laser treatment stimuli in EMs but not PMs of sparteine. Clin Pharmacol
22. Williams D, Patel A, Howard R. Pharmacogenetics of codeine
metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth
23. Chen Z, Somogyi A, Bochner F. Polymorphic demethylation of codeine
24. Eckhardt K, Shuxia L, Ammon S, et al
. Same incidence of adverse events after codeine
administration irrespective of the genetically determined differences in morphine
25. Poulsen L, Brasen K, Arendt-Nielsen L, et al
in extensive and poor metabolizers of sparteine. Eur J Clin Pharmacol
26. Leith B. Pharmacological management of pain
after intracranial surgery. J Neurosci Nurs
27. Rivet M. The use of IV codeine
in the neurosurgical patient population. J Can Assoc Crit Care Nurs
28. Austin K, Stapleton J, Mather L. Multiple IM injections. Pain
29. Semel J. Fever associated with repeated IM injections of analgesics
. Rev Infect Disease
30. Quiney N, Cooper R, Stoneham M, et al
- a time for reappraisal? Br J Neurosurg
31. Ng K, Tsui J, Yang S, et al
. Increased nausea and dizziness when using tramadol for postoperative
PCA compared with morphine
. Eur J Anaesthesiol
32. Pang W, Mok M, Lin C, et al
. Comparison of PCA with tramadol or morphine Can J Anaesth
33. Jeffrey H, Charlton P, Mellor D, et al
after intracranial surgery: a double blind prospective comparison of codeine
and tramadol. Br J Anaesth
34. Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effect of 50 and 100 mg oral tramadol after orthopaedic surgery. Pain
35. Stamer U, Maier C, Grondt B, et al
. Tramadol in the management of post operative pain
: a double blind, placebo and active drug controlled study. Eur J Anaesthesiol
36. Herbert C. Use of morphine
after intracranial surgery. Professional Nurse
37. Kathirvel S, Dash H, Bhatia A, et al
. Effect of prophylactic ondansetron on post-operative nausea and vomiting after elective craniotomy
. J Neurosurg Anaesth
38. Gardner J, Blough D, Drinkard C, et al
. Tramadol and seizures. Pharmacotherapy
39. Jick H. The risks of seizure associated with tramadol. Pharmacotherapy
40. Cold GE, Felding M. Even small doses of morphine
might provoke ‘luxury perfusion’ in the postoperative
period after craniotomy
41. Vickers M, Szekely S, Read M, et al
. Tramadol: pain
relief by an opioid without fear of depression of respiration. Anaesthesia
42. Pasero C, McCaffery M. Avoiding opioid-induced respiratory depression. Am J Nurs
43. Carroll D. Pain
assessment. In: Carroll D, Bowsher D, eds. Pain Management and Nursing Care
. Oxford, UK: Butterworth Heinneman Ltd, 1993.
44. Voepel-Lewis T, Merkel S, Tait AR, et al
. The reliability and validity of the face, legs, activity, cry, consolability observational tool as a measure of pain
in children with cognitive impairment. Anesth Analg
45. Terstegen C, Koot HM, de Boer JB, et al
. Measuring pain
in cognitive impairment: pain
response to surgical procedures. Pain