EUROANESTHESIA 2008 Copenhagen, Denmark, 31 May - 3 June RC1

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1 PREVENTING PAIN IN NEUROSURGICAL PATIENTS EUROANESTHESIA 2008 Copenhagen, Denmark, 31 May - 3 June RC1 SABINE HIMMELSEHER, EBERHARD F. KOCHS Department of Anaesthesiology Technical University Munich Munich, Germany Saturday, May 31, :00-14:45 Room B5 Preventing postoperative pain and improving long-term outcome in neurosurgical patients is an enormous challenge. Only a very limited number of randomized, controlled trials on peri-operative treatment of pain in neurosurgical patients are available, let alone studies on long-term pain prevention [1-3]. Pain after craniotomy remains inconsistently recognised and seems poorly treated in the postoperative period [4]. Nevertheless, postcraniotomy pain is known to be moderate to severe depending on the specific procedure and site of surgery [1-5]. The dilemma in providing sufficient pain therapy after craniotomy mainly results from conflicting treatment goals and specific, disease-related conditions: on one hand, intracranial surgery patients require frequent postoperative neurological examinations, and on the other adequate postoperative therapy using opioid analgesics may result in excess sedation, neurocognitive status may be depressed and postoperative intracranial complications become masked. In addition, inadequate pain treatment may be associated with agitation and sympathetic stress responses, which increases the risk of hypertension, intracranial haemorrhage, intracranial pressure rise and other neurological threats after brain surgery [1-3]. Patients undergoing spinal surgery often suffer from severe pre-operative pain and may require large doses of analgesic drugs including opioids. Longer-lasting, pre-operative or chronic pain of greater intensity have been identified as specific risk factors for severe postoperative pain that is difficult to treat [1, 2], and repeated surgery and anxiety may predispose patients with failed back syndrome to problematic postoperative pain control. Because neurological examination to detect spinal cord complications requiring immediate intervention are based upon patient co-operation and awareness, different modalities for postoperative pain treatment and a choice of drugs from various classes of analgesics may be effective in these circumstances. Overall, severe postoperative pain has been correlated with an increased risk for the development of persistent, chronic pain states [6, 7]. EVIDENCE FOR LONG-TERM PAIN PREVENTION IN THE GENERAL SURGICAL POPULATION Therapy for lasting pain prevention not only aims at peri-operative inhibition of peripheral and central pain sensitization and prevention of hypersensitive nociception, but is also directed at improving rehabilitation and long-term outcome [6, 7]. While pre-emptive analgesia is mainly targeted at blockade of nociceptive signal transduction before tissue injury, pain preventative strategies encompass approaches that reduce sensitization phenomena for as long duration and as effectively as possible. Progress in basic knowledge about post-injury central nervous system plasticity and pain memory, and recent insight from new incisional pain models showing continued pain generation from surgical wounds [6-8] support the principle that pain preventative strategies may be required that last into the postoperative period. Although analysis of trials on epidural anaesthesia/analgesia or peripheral nerve blockade techniques show that acute postoperative pain relief is improved compared with traditional opioid use, long-lasting analgesic efficacy remains controversial, and a recent meta-analysis demonstrated no effect on long-term outcome [9-11]. Nevertheless, meta-analyses and trials of multimodal combination regimens to prevent pain indicate promising results [11]: IV sub-anaesthetic dose ketamine administered with perioperative epidural analgesia has been shown to reduce postoperative pain and to prevent one year residual pain in patients undergoing colorectal cancer surgery [12]; postoperative oral gabapentin combined with local anaesthetic wound infusion diminished early postoperative and one month pain after abdominal hysterectomy [13]; and peri-operative intravenously administered low-dose lidocaine facilitated rehabilitation after laparoscopic colectomy [14]. Thus, at present, there is limited but definitive clinical evidence for long-term effectiveness of pain preventative measures on patient outcomes in certain surgical settings. Use of different pain treatment modalities directed at targeting nociceptive, inflammatory, and neuropathic components of tissue injury and advanced surgical techniques are associated with long lasting benefits on recovery from surgery [6, 7]. ANALGESIC THERAPY AFTER CRANIOTOMY Pain after craniotomy appears to be somatic, mainly originating from the scalp, pericranial muscle and soft tissue injury, or from manipulation of the dura mater. The site of craniotomy and the extent of the procedure correlate with the pain experienced by the patient, with subtemporal and suboccipital surgery frequently causing severe, postoperative pain [2, 6]. In addition to concerns about the deleterious effects of both analgesic drugs

2 and poorly treated pain on the post-surgical brain, there are some important considerations to take into account before antinociceptive options can be discussed [3]: there are no standardized or pro-active protocols for the evaluation of post-craniotomy pain, analgesic therapy, or patient and carer education; physicians are confronted with the difficulties of diagnosing pain and its severity in patients with aphasia, altered mental status, or cognitive impairment; and the continuing controversy regarding the choice of best anaesthetic regimen for intracranial surgery is associated with various practices and use of different anaesthetics and analgesics. These drug combinations have effects that last beyond the immediate intra-operative period. For example, the intraoperative use of fentanyl or sufentanil as compared with remifentanil has a direct impact on post-craniotomy pain. Remifentanil allows for rapid emergence from anaesthesia, but may be associated with opioid tachyphylaxis and increased postoperative pain. In the majority of patients undergoing intracranial surgery, transitional and potent early postoperative analgesia is required when remifentanil has been used intra-operatively [2, 3]. As a result of these factors a uniform approach to post-craniotomy pain evaluation and treatment is precluded. LOCAL ANAESTHETIC AGENTS Analysis of the small number of available, small controlled clinical trials on pain treatment after intracranial surgery shows that regional analgesia (either scalp block or wound infiltration) is often used as a first-line approach for post-craniotomy pain [2, 3]. In particular scalp blocks have been used in patients undergoing awake procedures or for provision of transitional analgesia after use of remifentanil. The major advantage is a lack of interference with neurological examination. Pre-incisional LA wound infiltration is often administered to blunt haemodynamic responses and to minimise bleeding from the skin incision (by the addition of epinephrine). However, if scalp blocks or wound infiltration are used prior to incision either no or only minor analgesic effects on postoperative pain have been observed. If used after skin closure, a temporary reduction in pain in the immediate and early postoperative period may be achieved. There appears to be a trend for lower pain scores and a better opioid sparing effect following scalp blocks compared with wound infiltration [3]. Recommended maximum doses for the LA agent must be strictly followed with either technique and intravascular injections with their risk for seizure induction must be avoided. PARENTERAL OPIOIDS Use of parenteral opioids for postoperative analgesia in spontaneously breathing craniotomy patients has often been viewed as impossible, mainly because of fears of excess sedation and respiratory depression. Nevertheless, opioids may become necessary when LA and less potent analgesics fail to achieve sufficient pain relief. Trials on morphine, codeine, and oxycodone have demonstrated that these opioids produce effective pain relief in post-craniotomy patients [1-3]. Unfortunately, morphine, codeine and other analgesics have often been delivered via the intramuscular route after intracranial surgery. This is of questionable value due to the uncontrolled, variable drug absorption from muscle tissue. Moreover, the continuing use of codeine as the preferred analgesic choice after craniotomy appears to be a relic of the past before pulse oximetry monitoring or naloxone were available. Codeine is a pro-drug, and its analgesic efficacy is derived from the 5-15% of the administered dose that is metabolized by hepatic CYP2D6 enzymes [3]. This process, and thus the efficacy of codeine, is remarkably affected by inter-individual and ethnic differences, with the result of very variable analgesic effects. Although it may be a tradition in some institutions IM codeine should no longer be used after craniotomy. The analgesic effects of IM codeine have been compared with those of IM tramadol [1, 3]. Breakthrough pain occurred more often after tramadol, and at higher tramadol doses the frequency of postoperative nausea and vomiting (PONV) increased. Use of an intravenous oxycodone PCA has also been reported after craniotomy [3]. Satisfactory analgesia without an increase in sedation was observed. All trials on post-craniotomy analgesic therapy are hugely underpowered with respect to evaluation of safety or toxicity. Opioid use carries inherent risks for serious complications after intracranial surgery in spontaneously breathing patients. However, opioid analgesia may be necessary to achieve adequate pain control. With careful patient monitoring and prudent titration to individual patient needs opioids may be used after brain surgery. Indeed, to prevent dangerous hypertension due to severe pain after remifentanil-based anaesthesia, potent opioids may be indispensable. Postoperative hypertension during emergence from anaesthesia and in the early period after intracranial surgery may be very dangerous for the brain and has been associated with an increased risk of intracranial haemorrhage [1-3]. OTHER ANALGESIC AGENTS Non-steroidal anti-inflammatory drugs (NSAIDs) such as paracetamol or ketoprofen are also used in neurosurgical patients but may cause platelet dysfunction and increase bleeding times. Because bleeding may be devastating after neurosurgery, non-selective NSAIDs should be used very carefully in the early post-craniotomy period. In high-risk situations, such as after aneurysm repair, arterio-venous malformation resection, or haematoma evacuation, NSAIDs should be avoided. In contrast to children, repeated use of paracetamol may not be sufficient for adequate pain relief in adult postcraniotomy patients [3]

3 There is little data on other drugs or methods with established analgesic efficacy after intracranial surgery. Intravenous sub-anaesthetic dose ketamine combined with LA scalp infiltration attenuates haemodynamic responses to skull-pin placement [2, 3]. Although it does not cause an intracranial pressure rise in neurosurgical patients when used during controlled ventilation [15], ketamine is still used reluctantly during intracranial surgery because it may induce psychomimetic side-effects. In summary, the current limited data on analgesic therapy in the early postoperative period after craniotomy does not allow the production of evidence-based therapeutic standards or treatment guidelines to manage pain acutely or to prevent long-term post-craniotomy pain. There are no large trials on drug safety or efficacy issues, let alone standardised pain measurement tools. Investigations on approaches to pain management in adults with neurocognitive impairment have not been published. Nevertheless, inadequate analgesia after intracranial surgery is recognized as a critical determinant for development of persistent post-craniotomy headache [3]. ANALGESIC THERAPY AFTER SPINAL SURGERY In spinal surgery patients acute or chronic back pain may originate from many structures, including the vertebrae, intervertebral disks, dura and nerve root sleeves, facet joint capsules, muscles, fascia, and ligaments. Inflammation or mechanical nerve compression may cause local and widespread pain. Referred pain is mostly neuropathic and may exceed local pain. Often it is relieved by anticonvulsant or antidepressant medications. Postoperative pain after surgery on the spine is proportional to the number of operated vertebrae and the invasiveness of the procedure, and many patients experience moderate to severe pain [1, 2]. In addition to the use of appropriate analgesic approaches to postoperative pain, patients require early postoperative mobilisation and functional rehabilitative measures. Analysis of the limited data from the often small clinical trials demonstrates that excessive reliance on parenteral opioid-only analgesia does not usually provide optimal analgesia after spinal surgery [1, 2]. The doses needed to achieve satisfactory pain control cause many unpleasant, opioid-related adverse effects. While an opioid PCA may be used as the analgesic base, a regimen based on a combination of drugs is more appropriate. Among the NSAIDs ketorolac has often been investigated in spinal surgery trials [2] and may provide an effective opioid-sparing effect. Paracetamol may be given as an alternative. In patients with haemostatic disturbances, COX-2 inhibitors such as celecoxib may aid postoperative pain reduction and decreased opioid requirements [16]. Nevertheless, lack of clarity about serious adverse effects of highdose NSAIDs on skeletal repair processes have caused controversy with respect to their use in procedures requiring bone healing [17]. CENTRAL NEURAXIAL TECHNIQUES In view of the advantages of neuraxial techniques on postoperative pain control, stress reduction, and functional recovery in general surgical settings, intrathecal (IT) and epidural analgesic methods have been investigated for spinal procedures [2, 18]. For early postoperative pain therapy, IT opioids have emerged as a first-line option, and are readily available with the surgeon administering the drug as long as the intrathecal sac is exposed [1, 2, 18]. Use of preservative-free morphine has evolved as the preferable opioid choice, mainly because it has a relatively long duration of action. However, IT morphine may cause sedation and respiratory depression and adequate postoperative monitoring must be undertaken. To improve analgesia while reducing the opioid dose, IT opioids may be combined with either LA or clonidine, but care must be taken not to prolong the motor block. Epidural techniques with various modes of drug delivery such as single and double catheters, PCA or continuous infusion devices have been used after spine surgery [1, 2, 18, 19]. Potential advantages from the use of epidural LA and/or epidural opioids include superior analgesia, more rapid recovery, better pulmonary function, earlier oral intake and return of bowel movements, and a shorter duration of hospital stay compared with placebo or parenteral opioid analgesia [1, 2, 18, 19]. However, other studies have failed to demonstrate these beneficial effects of epidural techniques or even reported an increased frequency of systemic complications such as hypotension [1, 2]. These divergent observations may be explained by differences in the epidural administration methods applied (intermittent bolus vs. continuous infusion vs. PCA with or without a background infusion), the drugs used, doses and combinations used, and a variety of other differences between the trials (such as various surgical procedures). Other analgesic drugs such as alpha-2 agonists have been used as epidural adjunctive agents. Because epidural clonidine is known to reduce neuropathic pain, the use of a double epidural catheter approach with insertion of one catheter cranial and one caudal to the surgical field and continuous infusion of bupivacaine, fentanyl, and clonidine has been investigated [20]. Not surprisingly, this multimodal analgesic strategy provided superior postoperative pain relief, with no pain at rest and a low incidence of adverse effects. This technique may serve as a rationale for further refinement of therapeutic concepts. Taken together, the available studies on neuraxial analgesia for managing pain after spinal surgery report many differences in analgesic efficacy, pain relief and other variables and at present it is not possible to decide which method or drug combination is best. However, the prudent use of epidural analgesia and selection of drugs and administration schedules may provide good analgesia and may be associated with better long-term functional recovery

4 To optimize drug combination concepts trials have evaluated regimens that combine modalities and drugs from two or more different classes of agent. Two recent examples are the combination of peridural methylprednisolone and wound infiltration with LA which was reported to reduce pain after lumbar spinal surgery [21], and the combination of pregabalin and celecoxib which reduced postoperative pain after spinal fusion surgery more than either drug alone. Overall, trial data on analgesic therapy after spinal surgery is limited. Data are confounded by methodological weaknesses and there is a wide difference in management practices. We lack comparisons of equi-analgesic treatment approaches and evidence-based guidelines cannot be written. Research efforts should, therefore, be directed towards conducting sufficiently powered trials with functional and longterm endpoints that are appropriate to reflect the effects of pain preventative strategies. A PROPOSAL: PAIN PREVENTATIVE STRATEGIES FOR NEUROSURGICAL PATIENTS To provide a pain preventative strategy for the neurosurgical patient undergoing intracranial or spinal surgery we would like to propose two simple pathways (Figures 1 and 2). The development of these pathways has been based on the evidence that supports the notion that effective postoperative pain reduction of sufficient duration may provide long-term benefits for patient well-being [6-8, 11-14]. As an underlying rationale the current view that using multiple analgesic techniques is best practice for achieving pain prevention has been incorporated [6, 7, 22]. When designing a pro-active treatment plan for postoperative pain prevention it is important to decide whether the procedure is expected to be painful, whether the patient has other risk factors for severe postoperative pain and whether painful rehabilitative measures will be performed. Minimally invasive surgery and surgical techniques that avoid nerve damage are preferred. These pathways are presented for stimulation of thought and further practice improvement. FIGURE 1. PROPOSAL FOR A PAIN PREVENTATIVE APPROACH FOR INTRACRANIAL SURGERY. Suggested techniques and drugs may only be used if there are no specific contraindications; all interventions must be applied with close attention to interference with other therapies and individual patient circumstances. NMDA = N-methyl-D-aspartate antagonist

5 FIGURE 2. PROPOSAL FOR A PAIN PREVENTATIVE APPROACH FOR SPINAL SURGERY. Suggested techniques and drugs may only be used if there are no specific contraindications; all interventions must be applied with close attention to interference with other therapies and individual patient circumstances. CONCLUSION Although evidence from trials tends to lag behind clinical practice, this work shows the many deficiencies of the existing literature on pain management in the neurosurgical patient. Nevertheless, severe postoperative pain impairs the quality of recovery and causes emotional distress with the possibility of inducing chronic pain and lasting functional deficits. Much more investigational work is therefore warranted to improve analgesic therapy after n e u r o s u rg e r y. It is reported that postoperatively the general surgical population benefits from early oral fluid intake, enteral nutrition, forced mobilization, and improved pain and PONV management. However, there is a sense that pain preventative strategies will not be the only development for improving care. As the evolution of analgesic therapy develops with general progress in patient management, the next phase of trials may be driven by the overall goal of accomplishing the best physiological recovery within multidisciplinary, peri-operative pathways. When all of these processes have been optimised in the treatment of patients after intracranial or spinal surg e r y, it may no longer be possible to demonstrate discernible beneficial effects of dedicated pain preventative strategies in isolation

6 KEY LEARNING POINTS There is little evidence, let alone pro-active protocols, for pain prevention, pain treatment, or longterm outcome improvements in the peri-operative care of neurosurgical patients. 80% of patients experience moderate to severe pain after intracranial or spinal surgery which often persists for several days. With careful monitoring and prudent titration to individual patient needs, IV opioids may be used for analgesia. When the intensity of pain is expected to be high with intracranial surgery, consider intra-operative fentanyl or sufentanil; scalp nerve blocks before incision and / or before extubation; and low-dose NMDA-antagonist. After intracranial surgery, use opioids with meticulous monitoring; non-pharmacological methods; and, if not contraindicated, NSAIDs after a time safety margin. When the intensity of postoperative pain is expected to be high with spinal surgery, consider intraoperative fentanyl or sufentanil; low-dose ketamine; and, at the end of surgery, epidural analgesia with an LA-opioid combination or a wound catheter with LA alone. After spinal surgery, use an epidural PCA (with a background infusion of LA), or a wound catheter with LA infusion; if an epidural or wound catheter is not available use IV PCA; consider very lowdose ketamine; consider gabapentin or pregabalin; COX-2 inhibitors or, if not contra-indicated, NSAIDs; non-pharmacological techniques. REFERENCES 1. Deer TR. Management of pain in the neurosurgical patient. In: Handbook of neuroanesthesia. Newfield P, Cottrell JE, eds. Philadelphia: Lippincott Williams & Wilkins, 2007: Ortiz-Cardona J, Bendo AA. Perioperative pain management in the neurosurgical patient. Anesth Clin 2007; 25: Nemergut EC, Missaghi NB, Durieux ME, Himmelseher S. Pain management after craniotomy. Best Practice & Research Clinical Anaesthesiology 2007; 21: Durieux M, Himmelseher S. Pain control after craniotomy: off balance on the tightrope. J Neurosurg 2007; 106: Thibault M, Girard F, Moumdjian R, Chouinard P, et al. Craniotomy site influences postoperative pain following neurosurgical procedures: a retrospective study. Can J Anesth 2007; 4: Reuben SS. Chronic pain after surgery: what can we do to prevent it. Current Pain and Headache Reports 2007; 11: Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367: Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006; 19: Nishimori M, Ballantyne JC, Low JH. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Systematic Reviews 2006; 3: CD Richman JM, Liu SS, Courpas G, Wong R, et al. Does continuous peripheral nerve block provide superior pain control to opioids. A meta-analysis. Anesth Analg 2006; 102: Himmelseher S, Kochs E. Preemptive analgesia does it work. Croatian Medical Journal 2008 (in press). 12. Lavand homme P, de Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology 2005; 103: Fassoulaki A, Melemeni A, Stamatakis E, Petropoulos G, et al. A combination of gabapentin and local anaesthetics attenuates acute and late pain after abdominal hysterectomy. Eur J Anaesth 2007; 24: Kaba A, Laurent SR, Detroz BJ, Sessler DI, et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology 2007; 106: Himmelseher, S, Durieux M. Revising a dogma: ketamine for patients with neurological injury. Anesth Analg 2005; 101: Reuben SS, Buvanendran A, Kroin JS, Aghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg 2006; 103: Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anesth 2005; 52: Tobias JD. A review of intrathecal and epidural analgesia after spinal surgery in children. Anesth Analg 2004; 98: Schenk MR, Putzier M, Kügler B, Tohtz S, et al. Postoperative analgesia after major spine surgery: patient-controlled epidural analgesia versus patient-controlled intravenous analgesia. Anesth Analg 2006; 103: Ekatodramis G, Min K, Cathrein P, Borgeat A. Use of a double epidural catheter provides effective postoperative analgesia after spine deformity surgery. Can J Anesth 2002; 49: Jirarattanaphochai K, Jung S, Theinthong S, Krisanaprakornkit W, et al. Peridural methylprednisolone and wound infiltration with bupivacaine for postoperative pain control after posterior lumbar spine surg e r y. Spine 2007; 32: Pyati S, Gan TJ. Perioperative pain management. CNS Drugs 2007; 21: