Year : 2015 | Volume
: 29 | Issue : 1 | Page : 9--14
Pain Management After Spinal Surgery
A Rudra1, Suman Chaterjee2, S Ray3, S Ghosh4,
1 Professor of Anaesthesiology, K.P.C. Medical College, Kolkata, India
2 Associate Professor of Anaesthesiology, Midnapore Medical College, Paschim Midnapur, India
3 Consultant Anaesthesiologist, K.P.C. Medical College, Kolkata, India
4 Fellow of Anaesthesia and Critical Care, Tata Medical Center, Kolkata, West Bengal, India
Department of Anaesthesiology, Midnapore Medical College, Midnapore, West Bengal
One of the most important cause of postoperative morbidity is insufficiently treated pain. Patient undergoing spinal surgery often suffer from severe preoperative pain and may require large doses of analgesic drugs including opioids. Longer-lasting, preoperative or chronic pain of greater intensity, patients with «SQ»failed back syndrome«SQ» have been identified to cause problems towards control of postoperative pain. Because neurologic examination to detect spinal cord complications requiring immediate intervention are based upon patient cooperation 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, moderate to severe postoperative pain has been correlated with an increased risk for the development of persistent, chronic pain states. These problems may be prevented by successful management of postoperative pain. Acute postoperative pain management is a dynamic process. A detailed preoperative assessment should be done at the beginning and the most appropriate pain management should be provided by utilizing the newer drugs and techniques after estimation of risk-benefit status for each patient.
|How to cite this article:|
Rudra A, Chaterjee S, Ray S, Ghosh S. Pain Management After Spinal Surgery.Indian J Pain 2015;29:9-14
|How to cite this URL:|
Rudra A, Chaterjee S, Ray S, Ghosh S. Pain Management After Spinal Surgery. Indian J Pain [serial online] 2015 [cited 2020 May 28 ];29:9-14
Available from: http://www.indianjpain.org/text.asp?2015/29/1/9/145916
Postoperative pain is a form of acute pain that starts with surgical trauma with an inflammatory reaction and irritation of an afferent neuronal barrage and ends with tissue healing. It is influenced by cultural, social, and psychological factors of the patient. Moreover, patients often consider "postoperative pain" the most frightening aspect of undergoing surgical procedure. Furthermore, these patients may have been receiving long-term narcotic therapy and may have developed a tolerance to narcotics. Therefore, an individual assessment of pain and provision of analgesic therapy are essential. In addition, before prescribing the analgesics medical condition, physical condition, age, level of fear or anxiety, personal preference, and response to agent should be considered. Otherwise, failure to adequate management of postoperative pain can have combined constellation of several unpleasant sensory, emotional experiences, and associated with autonomic hyper reactivity (increased heart rate, blood pressure, suppression of gastrointestinal mobility), reduced mobility (muscle wasting, joint stiffening), endocrine-metabolic, psychological and behavioral responses (depression, helplessness, anxiety).  Inadequate management of postoperative pain i.e. prolongation of pain during postoperative period would lead to sensitization of central and peripheral nervous system. 
Following spine surgery, majority of patients report moderate to severe pain, which persists for at least for initial 3-4 days. , The pain is proportional to the number of operated vertebrae and the invasiveness of the procedure. , There seems to be no significant difference in the severity of pain between cervical, thoracic, and lumbar spine surgeries. ,, Minimally invasive neurosurgical techniques are associated with minimum postoperative pain. ,
Early ambulation to facilitate surgical outcome, adequate pain relief with patient safety are essential. Analyses of limited data from the available reports of clinical trials demonstrate that many patients still suffer from pain despite focusing on pain management programmes.
Multimodal Approaches 
As the postoperative pain is complex problem, it is almost impossible to control pain with unimodal approaches. Rational approach to the treatment of postoperative pain is therefore to combine different treatment modalities, working at different pain mechanisms, to improve analgesia and potentially to reduce side effects. Thus, for past 15 years, multimodal approaches have been applied in clinical practice with local anesthetics, anti-inflammatory drugs, and antihyperalgesics seems rational. So far, the combination of epidural local anesthetics with opioids along with parenteral non-sterioidal anti-inflammatory drugs (NSAIDs), or paracetamol with NSAIDs has been demonstrated to provide adequate postoperative analgesia.
Treatment Methods 
These include systemic analgesics and regional analgesic techniques. Preferences of the patient should be considered by the clinicians while evaluating individual benefits and risks of each treatment to provide the best postoperative pain regimen. ,,
In this article, we will discuss the different modalities with various classes of pain relievers commonly employed as postoperative analgesic after spine surgery. The range of medications available for treating postoperative pain continues to grow. Although opiate medications are commonly considered the "gold standard" of analgesics, however, the patient needs constant vigilance due to the serious undesirable effects associated with the opiates.
Selecting the most appropriate analgesic for the patient with pain after spine surgery poses a challenge to the anesthesiologists, given the staggering array of analgesics, each with specific indications, contraindications, pharmacological properties, and adverse effects. Therefore, an appropriate choice will depend on the patient's general physical condition and a complexity associated with the type of spine surgery.
The opioids provide analgesia whether given into the spinal cord or into higher centers. These agents have been used alone or in combination with other agents. The main disadvantages associated with opioids when used to achieve adequate analgesia including pruritus, sedation, respiratory depression, nausea and vomiting, feeling of apathy, orthostatic hypotension particularly if the patient is even slightly dehydrated.
The undesirable effects are observed in all of the opioids in varying degrees. The agonist antagonist combinations were developed in an attempt to limit the potential liabilities of opioids. However, propensity to increase cardiac work and psychotomimetic potential has limited their use.
Minimal dose of opioid should be used as a part of multidrug approach to provide better satisfaction of patient with decreased risk of undesirable effects. ,
Non-steroidal anti-inflammatory drugs (NSAIDs)
These agents show their analgesic and anti-inflammatory effects by inhibiting prostaglandin synthesis. NSAIDs block inflammatory cascade and cyclooxygenase and lead to reduction in pain, fever, platelet aggregation, and inflammatory responses.  Sole use of NSAIDs cannot provide adequate pain relief following spine surgery. However, combination of NSAID with opioids gives better results than either one alone. , In patients with hemostatic disturbances, COX-2 inhibitors such as celecoxib may aid postoperative pain reduction and decreased opioid requirements.  In the postoperative setting, NSAIDs are more effective than paracetamol.
Pain reduction with acetaminophen primarily depends on its central mechanism. Although acetaminophen has antipyretic and analgesic effects, its anti-inflammatory effect is negligible. However, acetaminophen has lesser side effects in comparison with others.
Intravenous paracetamol is the pro-drug of acetaminophen, recently available in our country. Alone, paracetamol cannot control moderate and severe postoperative pain however in combination decrease opioid requirement by 40-50%. , Moreover, paracetamol may be a useful alternative as an adjuvant along with opioids in which other NSAIDs may be contraindicated.  However, paracetamol alone was not effective in reducing postoperative pain after lumbar disc surgery at 48 hours. 
Ketorolac, the other parenteral NSAID available is a non-specific inhibitor of both cyclooxygenase isoenzymes (Cox 1 and Cox 2) used as an adjuvant to opioids to relieve acute postoperative pain after spine surgery due to delayed onset of action. , However, early stages of bone healing may be delayed as the agent decrease formation of PGE2. 
Newer NSAIDs have been sought in hope of increasing analgesic and anti-inflammatory potency, while minimizing side effects. Unfortunately, most of these agents increase the risk of bleeding by decreasing platelet adhesiveness and increased bleeding times. Because bleeding may be dangerous after spine surgery, non-selective NSAIDs should be used very carefully in the early postoperative period. The NSAIDs alter prostaglandin production, and this directly affects renal function. Respiratory depression generally is not associated with NSAIDs.
Other analgesic drugs
Corticosterioids intravenously could be considered to reduce postoperative pain after spinal surgery. King JS has recommended that a lower dose of dexamethasone 10 mg intravenously during surgery helped to reduce analgesic requirements in patients undergoing lumber discectomy. Larger trials are needed to confirm or refute these findings. 
Ketamine, is an N-methyl -d- aspartate (NMDA) antagonist. NMDA antagonists block the glutamine receptors in the dorsal root; this plays an important role in sensitization process  after noxious stimuli. In subanesthetic dose, ketamine may lead to selective non-competitive NMDA blockage. Therefore, ketamine with low dose could effectively relieve pain following surgery  and decrease consumption of opioid in opioid-dependents. , Adverse effects of this drug include increased salivation, sedation, nausea, dysphoria, and even hallucinations.
Gabepentin was found to be effective in decreasing 24-hour cumulative opioid consumption with acceptable adverse effects according to several trials. ,,
Intravenous Patient-Controlled Analgesia (PCA)
Inadequate pain relief is frequently experienced by the patient due to delay in administration of the analgesic agent, especially analgesic injection when needed conventionally, based on the demand of the patient.
Great changes occur in plasma drug concentration profile develops following opioid administration vial intramuscular or infusion route for postoperative pain relief. This viability leads to inadequate effectiveness of intramuscular administration of opioids for postoperative pain relief. On the other hand, nurses' acting conservatively due to abstaining from side effects that may develop during narcotic use have led to seeking safer and more effective methods for postoperative analgesia. Patient-controlled analgesia has been used both, as a means of treating pain and a means of quantifying analgesic deficit. Therefore, PCA allows the patient to control the delivery of analgesic and provides superior pain relief by administration of continuous background infusion superimposed on boluses by using a small microprocessor-controlled pump to maintain the plasma level of the analgesic in a relative constant state and to eliminate the undesirable effects caused by fluctuations in plasma levels of the analgesic. When choosing a drug for PCA administration, the ideal drug should be highly efficacious, have a rapid onset of action, and a moderate duration of effect. The ideal drug should not accumulate or change pharmacokinetic properties with repeated administrations and should have a large therapeutic window. Pediatric patients especially have pain severity that is under estimated by nursing personnel, and these patients benefit greatly from the use of PCA.  This technique has been shown effective in patients as young as 11 years old. 
The most widely prescribed drug through this mode is morphine, in the dose of 1-1.5 mg with a lock-out period of 5-10 minutes. However, regular review is needed in every patient to ensure that pain relief is adequate. Patients who use this drug by PCA pump they reach a level of comfort, however, that usually is in balance between acceptable pain with minimal undesirable effects.
In PCA therapy, patients titrate their own need for analgesic to relieve the postoperative pain. Therefore, they must be able to activate the device and be willing to participate in their own treatment plan. Otherwise, some problems will be encountered during postoperative pain relief with PCA technique. Furthermore, the patient should be appropriately oriented to its proper usage. This usually can be accomplished in the recovery room by a properly trained recovery-room nurse. Otherwise, some problems will be encountered during pain relief with PCA.
Regarding the incidence of respiratory depression and/or respiratory arrest in patients on PCA has not been much reported.
Central Neuraxial Technique
Neuraxial analgesic technique may be used for effective relief of pain and is superior to systemic opioids.  Moreover, pain relief through this route decrease morbidity and mortality. ,, Both opioids and local anesthetics can be provided by epidural or intrathecal route. Of these, epidural catheter infusion is the most commonly used method. However, for early postoperative pain therapy, intrathecal 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. ,, Use of preservative-free morphine has evolved as the preferable opioid of choice, mainly because it has a relatively long duration of action without any demonstrable motor, sensory or autonomic deficit. Intrathecal morphine may cause sedation and respiratory depression. Therefore, adequate postoperative monitoring must be undertaken.
The advantages of epidural opioids or the combination of opioids and local anesthetics include low pain scores,  decreased parenteral opioid requirements,  and better patient satisfaction. Among the local anesthetics ropivacaine is the choice of agent due to its longer duration of action, safety, and selectivity toward sensory blocked without motor blockade. The most commonly used opioid for epidural analgesia is morphine. It was observed to show analgesic efficiency, even in very low blood concentrations after epidural administration.  It accumulates in cerebrospinal fluid due to its highly hydrophilicity. Low doses should be initiated in the elderly patients. Furthermore, opioids affect the modulation of nociceptive input by acting on receptors in the dorsal horn without producing motor or sympathetic blockade. Hence, opioids are useful in the pain management following spine surgery because motor and sensory functions are closely monitored during postoperative period. The advantages of the combination of local anesthetic and opioids are a synergistic effect with lower opioid doses and overall fewer side effects. 
Ideal way for epidural administration is intermittent injections. Otherwise, with an infusion technique, there is a risk for catheter migration, potential sympathetic block, and orthostatic hypotension.
Definite contraindication to neuraxial techniques of proving analgesia include coagulopathy and systemic infection associated with bacteremia. However, a patient with anticoagulation therapy is relative contraindication of this technique. The timing of the epidural catheter removal is important as most case reports of epidural hematoma have been demonstrated upon removal of the epidural catheter.
Nurses' monitoring the patients being well educated is also an important factor for choosing the technique. Standard orders for medications such as antiemetics (droperidol, 5HT 3 serotonin antagonists, etc.), antipruritus (diphenhydramine, etc.) greatly facilitate the delivery of postoperative care.
Analgesic Adjuvants (Clonidine, Dexmeditomidine)
As adjuvants alpha-2 agonists have been used to potentiate the actions of local anesthetics, opioids, or the combination for epidural analgesia due to their analgesic properties and increasing the effects of local anesthetics. Furthermore, the other advantages of above-mentioned agents as analgesic adjuvants used epidurally include minimal respiratory depression with stable hemodynamics and also reduction if oxygen need. Reported common side effects associated with epidurally administered clonidine include bradycardia, hypotension, and sedation.  However, clonidine (150 mcg) through epidurally in addition to bupivacaine subcutaneously at the incision site, provide postoperative analgesia and hemodynamic stability in the patient following lower spine surgery. 
Dexmeditomidine is a highly selective alpha-2 adrenergic agonist. It has greater affinity toward receptors compared to clonidine. It reduces the undesirable effects of opioids and local anesthetics by reduction in requirement of analgesic. However, randomized control trials with dexmeditomidine involving spine procedure are needed for its recommendation in the present article.
Extended Release Epidural Morphine (EREM)
This new drug called DepoDur applied as a single dose seems close to the analgesic targets. This drug was formulated for a one-time dose, administered epidurally at lumber level. Duration of effects may be prolonged up to 48 hours with EREM. ,,, Systemic concentration of morphine is minimal with EREM due to very high hydrophilicity of EREM. Better patient activity levels could be achieved with this new drug compared with morphine.  However, common side effects of this drug include pruritus and respiratory depression,  treated with opioid antagonists. Elderly are susceptible to the effects of EREM, and close perioperative monitoring is required.
This EREM may be an alternative for the management of postoperative pain in spinal surgery. 
Postoperative pain is a clinical condition that should be treated accurately and completely. Severe postoperative pain impairs the quality of recovery and cause emotional distress with the possibility of inducing chronic pain and lasting functional deficits. Therefore, each patient should be determined according to the severity of the pain. Spinal surgery cause moderate to severe postoperative pain; therefore, adequate pain relief demand a 24-hour - a day - commitment to these patients. However, trial data on analgesic therapy after spinal surgery is limited, and there is a wide difference in management practices. Research efforts should, therefore, be directed toward conducting functional and long-term endpoints that are appropriate to reflect the effects of pain preventing strategies.
|1||Sinatra R. Cause and consequences of inadequate management of acute pain. Pain Med 2010;11:1859-71.|
|2||Coley KC, Williams BA, DaPos SV, Chen C, Smith RB. Retrospective evaluation of unanticipated admissions and readmissions after surgery and associated costs. J Clin Anesth 2002;14:349-53.|
|3||Bianconi M, Ferraro L, Ricci R, Zanoli G, Antonelli T, Giulia B, et al. The pharmacokinetics and efficacy of ropivacaine continuous would installation after spine fusion surgery. Anesth Analg 2004;98:166-72.|
|4||Cohen BE, Hartman MB, Wade JT, Miller JS, Gilbert R, Chapman TM. Postoperative pain control after lumbar spine fusion. Patient - Controlled analgesia versus continuous epidural analgesia. Spine (Phila Pa 1976) 1997;22:1892-6.|
|5||Deer TR. Management of pain in the neurosurgical patient. In: Newfield P, Cottrell JE, editors. 5 th ed. Handbook of Neuroanaesthesia. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 73-88.|
|6||Ortiz-Cardona J, Bendo AA. Perioperative pain management in the neurosurgical patient. Anesthesiol Clin 2007;25:655-74.|
|7||Bernard JM, Surbled M, Lagarde D, Trennec A. Analgesia after surgery of the spine in adults and adolescents. Cah Anesthesiol 1995;43:557-64.|
|8||Klimek M, Ubben JF, Ammann J, Borner U, Klein J, Verbrugge SJ. Pain in neurosurgically treated patients: A prospective observational study. J Neurosurg 2006;104:350-9.|
|9||Jaffe RA, Samuels SI. Anesthesiologist's manual of surgical procedures. 3 rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 189-204.|
|10||Oskouian RJ, Johnson JP. Endoscopic thoracic microdiscectomy. J Neurosurg Spine 2005;3:459-64.|
|11||Fessler RG, O'Toole JE, Eichholz KM, Perez-Cruet MJ. The development of minimally invasive spine surgery. Neurosurg Clin N Am 2006;17:401-9.|
|12||Beyaz SG, Bayer F, Erdem AF. Acute postoperative pain (Review Article). J Anesthe Clin Res 2011;S7-002:1-8.|
|13||Diatchenko L, Nackley AG, Tchivileva IE, Shabalina SA, Maixner W. Genetic architecture of human pain perception. Trends Genet 2007;23:605-13.|
|14||Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007;81:429-44.|
|15||Govoni S, Regazzi M, Ranjani GN. Pain and pharmacogenitics at the fuzzy border between phain physiotherapy and pain treatment. Eur J Pain 2008;2:5-12.|
|16||Jirarattanaphochai K, Thienthong S, Sriraj W, Jung S, Pulnitiporn A, Lertsinudom S, et al. Effect of parecoxib on postoperative pain after lumbar spine surgery: A bicenter, randomized double-blinded, placebo-controlled trial. Spine (Phila Pa 1976) 2008;33:132-9.|
|17||Gottschalk A, Durieux ME, Nemergut EC. Intra operative methodone improves post operative pain control in patients undergoing complex spine surgery. Anesth Analg 2011;112: 218-23.|
|18||Rao P, Knaus EE. Evolution of non-sterioidal anti-inflammatory drugs (NSAIDs) cyclooxygenase (cox) inhibition and beyond. J Pharm Pharm Sci 2008;11:81-110s.|
|19||Lai LT, Ortiz-Cardona JR, Bendo AA. Perioperative pain management in the neurosurgical patient. Anesthesiol Clin 2012;30:347-67.|
|20||Hans P, Brichant JF, Bonhomme V, Triffaux M. Analgesic efficiency of paracetamol hydrochloride after lumbar disc surgery. Acta Anaesthesiol Belg 1993;44:129-33.|
|21||Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg 2006;103:1271-7.|
|22||Dahi V, Raeder JC. Non-opioid post operative analgesia. Acta Anesthesiol Scand 2000;44:1191-203.|
|23||Taygar P, Akaya, T, Ozkan D, Ozel O, Uslu E, Gümüº H. Does intravenous paracetamol have preemptive analgesic effect on lumber disc surgeries? Agri 2008;20:14-9.|
|24||Le Roux PD, Samudrala S. Postoperative pain after lumber disc surgery: A comparison between ketorolac and narcotics. Acta Neurochir (Wein) 1999;141:261-7.|
|25||Turner DM, Warsen JS, Wirt TC, Scalley RD, Cochran RS, Miller KJ. The use of ketorolac in lumbar spine surgery: A cost-benefit analysis. J Spine Disord 1995;8:206-12.|
|26||O'Keefe RJ, Tiyapatanaputi P, Xie C, Li TF, Clark C, Zuscik MJ, et al. Cox-2 has a critical role during incorporation of structural bone allografts. Ann N Y Acad Sci 2006;1068:532-42.|
|27||King JS. Dexamethasone--a helpful adjunct in management after lumbar disccectomy. Neurosurgery 1984;14:697-700.|
|28||Ma QP, Woolf CJ. Noxious stimuli induce an N-methyl-D-aspartate receptor - Dependent hypersensitivity of the flexion withdrawal reflex to touch: Implications for the treatment of mechanical allodynia. Pain 1995;61:383-90.|
|29||Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology 2005;102:211-20.|
|30||Sharma S, Balireddy RK, Vorenkamp KE, Durieux ME. Beyond opioid - Controlled analgesia: A systemic review of analgesia after major spine surgery. Reg Anesth Pain Med 2012;37:79-98.|
|31||Hadi BA, Al Ramadani R, Daas R, Naylor I, Zelkó R. Remifentanil in combination with Ketamine versus remifentanil in spinal fusion surgery - a double blind study. Int J Clin Pharmacol Ther 2010;48:542-8.|
|32||Rusy LM, Hainsworth KR, Nelson TJ, Czarnecki ML, Tassone JC, Thometz JG, et al. Gabapentine use in pediatric apinal fusion patients: A randomized double-blind, control trial. Anesth Analg 2010;110:1393-8.|
|33||Iuran A, Karamanliogh B, Memis D, Hamamcioglu MK, Tükenmez B, Pamukçu Z, et al. Analgesic effects of gabapentine after spine surgery. Anesthesiology 2004;100:935-8.|
|34||Pandey CK, Sahay S, Gupta D, Ambesh SP, Singh RB, Raza M, et al. Preemptive gabepentine decreases postoperative pain after lumbar discectomy. Can J Anaesth 2004;51:986-9.|
|35||Weldon BC, Connor M, White PF. Nurse - Controlled vs. Patient - Controlled analgesia following pediatric scoliosis surgery. Anesthesiology 1991;75:935.|
|36||Brown RE Jr, Broadman LM. Patient - Controlled analgesia (PCA) for postoperative pain control in adolescents. Anesth Analg 1987;66:S22.|
|37||Popping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, Pogatzki-Zahn EM. Effectiveness and safety of postoperative pain management: A survey of 18925 Consecutive patients between 1998 and 2006 (2 nd revision): A database analysis of prospective raised data. Br J Anaesth 2008;101:832-40.|
|38||Wu CL, Fleisher LA. Outcomes research in regional anaesthesia and analgesia. Anesth Analg 2000;91:1232-42.|
|39||Hanna MN, Murphy JD, Kumar K, Wu CL. Regional techniques and outcome: What is the evidence ? Curr Opin Anaesthesiol 2009;22:672-7.|
|40||Tobias JD. A review a intrataecal and epidural analgesia after spinal surgery in children Anesth Analg 2006;103:1311-7.|
|41||Lawry KJ, Tobius J, Kittle D, Burd T, Gaines RW. Postoperative pain control using epidural catheters after anterior spinal fusion for adolescent scoliosis. Spine (Phila Pa 1976) 2001;26:1290-3.|
|42||Amarnath L, Andriwh JT, Gurd AR, Weiker GG, Yoon H. Efficacy of intermittent epidural morphine following posterior spinal fusion in children and adolescents. Clin Orthop Relat Res 1989;249:223-6.|
|43||Gustfsson LL, Friberg-Nielsen S, Garle M, Mohall A, Rane A, Schildt B, et al. Extradural and parenteral morphine: Kinetics and effects in postoperative pain. A controlled clinical study. Br J Anaesth 1982;54:1167-74.|
|44||Rockemann MG, Seeling W. Epidural and intrathecal administration of alph - 2- adrenoceptor agonist for postoperative pain relief. Schmerz 1996;10:57-64.|
|45||Jellish WS, Abodelly A, Fluder EM, Shea J. The effect of spinal bupivacaine in combination with either spinal clonidine and/or 0.5% bupivacaine administered at the incision site on postoperative outcome in patients undergoing lumbar laminectomy. Anesth Analg 2003;96:874-80.|
|46||Gambling DR, Hughes TL, Manvelian GZ. Extended - Release epidural morphine (DepoDur) following epidural bupivacaine in patients undergoing lower abdominal surgery: A randomized controlled pharmacokinetic study. Reg Anesth Pain Med 2009;34:316-25.|
|47||Viscusi ER Manvelian GZ. A randomized study of the serum pharmacokinetics of lower thoracic extended - Release epidural morphine (DepoDur) after lidocaine - Epinephrinie test dose administration in patients undergoing upper abdominal surgery. Int J Chin Pharmacol Ther 2009;47:659-70.|
|48||Hartrick CT, Hartrick KA. Extended - Release epidural morphine (DepoDur): Review and safety analysis. Expert Rev Neurother 2008;8:1641-8.|
|49||Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G; EREM study Group. Forty-eight hours of post operative pain relief after total hip arthroplasty with a novel, extended - Release epidural morphine formulation. Anesthesiology 2005;102:1014-22.|
|50||Carvalho B, Rihey E, Cohen SE, Gambling D, Palmer C, Huffnagle HJ, et al. Single-dose sustained-release epidural morphine in the management of postoperative pain after elective cesarean delivery: Results of multicenter randomized controlled study. Anesth Analg 2005;100:1150-8.|