2009; 12:679-684 • ISSN 1533-3159

Focused Review

Opioid Induced : Clinical Implications for the Pain Practitioner

Sanford M. Silverman, MD

Opioids have been and continue to be used for the treatment of . Evidence From: Comprehensive Pain supports the notion that can be safely administered in patients with chronic pain Medicine, Pompano Beach, FL. without the development of addiction or chemical dependency. However, over the past Address correspondence: several years, concerns have arisen with respect to administration of opioids for the treatment Sanford M. Silverman, MD of chronic pain, particularly non-. Many of these involve legal issues with respect Comprehensive Pain Medicine to diversion and prescription abuse. Amongst these, opioid induced hyperalgesia (OIH) 100 East Sample Rd is becoming more prevalent as the population receiving opioids for chronic pain increases. Suite 200 Pompano Beach, FL 33064 E-mail: OIH is a recognized complication of opioid therapy. It is a pro-nocioceptive process which [email protected] is related to, but different from, tolerance. This focused review will elaborate on the neurobiological mechanisms of OIH as well as summarize the pre-clinical and clinical studies Disclaimer: There was no supporting the existence of OIH. In particular, the role of the excitatory neurotransmitter, N- external funding in the methyl-D-aspartate appears to play a central, but not the only, role in OIH. Other mechanisms preparation of this manuscript. of OIH include the role of spinal dynorphins and descending facilitation from the rostral Disclosure: Dr. Silverman is a ventromedial medulla. The links between pain, tolerance, and OIH will be discussed with speaker for Reckitt-Benckiser. respect to their common neurobiology. Conflict of interest: None.

Manuscript received: Practical considerations for diagnosis and treatment for OIH will be discussed. It is crucial for 07/18/2008 the pain specialist to differentiate amongst clinically worsening pain, tolerance, and OIH since Revised manuscript received: the treatment of these conditions differ. Tolerance is a necessary condition for OIH but the 9/15/2008 converse is not necessarily true. Accepted for publication: 11/4/2008 Office-based detoxification, reduction of opioid dose, opioid rotation, and the use of specific Free full manuscript: NMDA receptor antagonists are all viable treatment options for OIH. The role of sublingual www.painphysicianjournal.com appears to be an attractive, simple option for the treatment of OIH and is particularly advantageous for a busy interventional pain practice.

Key words: Opioid hyperalgesia, hyperalgesia, tolerance, NMDA receptor antagonists, NMDA receptor induced hyperalgesia, spinal dynorphin induced hyperalgesia, descending facilitation and hyperalgesia, buprenorphine and hyperalgesia, opioid detoxification, office- based detoxification, complications of opioid therapy

Pain Physician 2009; 12:679-684

or several decades, opioids have been The concept of pain sensitization from the chron- considered integral components in the ic administration of opioids is often referred to as Ftreatment of chronic pain. Evidence supports opioid induced hyperalgesia (OIH). There is substan- the notion that opioids can be safely administered to tial evidence to support the fact that this does oc- patients with chronic pain without the development cur with chronic opioid therapy. OIH may complicate of addiction or chemical dependency. Major pain and the clinical course of pain treatment in a patient re- addiction organizations have endorsed this concept (1). ceiving opioids. Although the current clinical milieu

www.painphysicianjournal.com Pain Physician: May/June 2009: 12:679-684

emphasizes physician monitoring of addiction, abuse, Since tolerance is characterized by decreasing ef- and diversion, OIH is often overlooked as a potential ficacy of a drug, it can be overcome by increasing the complication of opioid therapy. dose. However, unlike tolerance, OIH cannot be over- As earlier as the nineteenth century, OIH was ob- come by increasing dosage since OIH is a form of pain served in patients receiving for pain. It was sensitization induced by the drug which occurs within recognized that a potent such as morphine the central nerve system (CNS) . Pain is worsened with could actually result in an increase in pain and was increased opioid dosing and is improved by reducing observed by Albutt in 1870: or eliminating the opioid. Tolerance is a necessary con- dition for OIH, but the converse is not true. Clinically “At such times I have certainly felt it a great re- this is an important distinction that has obvious rami- sponsibility to say that pain, which I know is an fications with respect to continued use of opioids in a evil, is less injurious than morphia, which may be given patient. an evil. Here experience is needed. Does morphia Basic Science Evidence of Opioid Induced tend to encourage the very pain it pretends to Hyperalgesia relieve? “…..in the cases in question, I have much reason Mao (6) has documented the occurrence of OIH to suspect that a reliance upon hypodermic mor- in laboratory animals. The commonly employed test is phia only ended in that curious state of perpetu- to examine the responses of rats, specifically the paw, ated pain” (2). to withdrawal tests in response to noxious stimuli af- ter receiving multiple boluses or a continuous infusion This article is a focused review of OIH neurobiol- of opioid. A comparison of dose response effects are ogy and its clinical implications for the pain practitioner. measured before and after administration of an opi- Practical guidelines are suggested for the clinical man- oid. With intrathecal morphine administration there agement of OIH. is progressive reduction in baseline nocioceptive pain thresholds (7). Similar findings have been seen in rats Tolerance Versus Pain Sensitization receiving boluses (8) and in animals receiving Tolerance is a pharmacologic concept. It occurs repeated administration (9). These preclinical when there is a progressive lack of response to a drug studies support the concept that there can be sensitiza- thus requiring increased dosing. Tolerance can occur tion to pain with concurrent administration of opioids. with a variety of drugs including opioids (3,4). Clinical Evidence of Opioid Induced Tolerance may not only develop to the analge- Hyperalgesia sia provided by opioids but also develop undesirable side effects which are seen with opioid administra- Supporting evidence has shown that OIH occurs tion such as pruritis, nausea, sedation, and respiratory clinically outside the laboratory, and is seen after intra- . operative infusion, resulting in decreased Sensitization to pain occurs in several areas of the opioid efficacy (10). Significant pain reduction has been nervous system involving the transmission of pain. Pe- demonstrated in patients who have been detoxified ripheral mechanisms have been well documented with from high dose opioids (11). When challenged with respect to neural injury involving mediators of inflam- cold pressor tests, opioid addicts maintained on meth- mation. This is known as primary hyperalgesia and is adone demonstrated increased pain sensitivity (12). seen clinically with peripheral nerve injuries. Second- There have also been a host of experimental studies in ary hyperalgesia, on the other hand, occurs “down- human volunteers and anecdotal reports of increased stream” from the initiating nocioceptive stimulus and pain sensitivity induced or observed with the concomi- peripheral injury. In the , wide dynamic tant use of opioids. These studies and the mechanisms range neurons become sensitized through a variety of of OIH have been extensively reviewed (13). mechanisms which may be mediated by neurotrans- Neurobiological Mechanisms for Opioid mitters such as calcitonin gene-related peptide, Va- Induced Hyperalgesia soactive Intestinal Peptide (VIP), Dynorphin (DYN), Cholcystokinin (CCK), Neuropeptide Y (NPY), and N- There are many proposed mechanisms for OIH in- methyl-D-aspartate (NMDA) (5). cluding 3 areas which will be discussed:

680 www.painphysicianjournal.com Opioid Induced Hyperalgesia

• The central glutaminergic system Clearly several distinct neurobiological mecha- • Spinal dynorphins nisms may exist for OIH. However, determining which • Descending facilitation mechanism(s) predominate in any given patient has important implications for the pain practitioner. More Central Glutaminergic System studies are needed to examine the interactions be- The majority of studies examining the mecha- tween the glutaminergic system, spinal dynorphin, nisms of OIH involve the systemic administration of and descending facilitation. opioids (6,7). The excitatory neurotransmitter NMDA Opioid Induced Hyperalgesia and plays a central role in the development of OIH. The Clinical Practice current data suggest that opioid induced desensiti- zation (pharmacological tolerance) and sensitization As shown, lack of efficacy may be seen with the (OIH), while distinct processes, may share common cel- administration of opioids for chronic pain. Common lular mechanisms in part mediated through activation solutions to this include opioid rotation, reduction of of the central glutamatergic system (7). the administered dose, or detoxification. However, a The role of NMDA can be summarized as follows: major dilemma faces the pain practitioner. Is the lack 1. NMDA receptors become activated and when in- of efficacy seen as a result of tolerance or OIH? The hibited, prevent the development of tolerance challenge is to distinguish between the 2 since the and OIH (14-16). treatment of each is quite different. In addition, the 2. The glutamate transporter system is inhibited, clinician must be able to distinguish between OIH and therefore increasing the amount of glutamate clinical exacerbation of preexisting pain. available to NMDA receptors (17). Several features of OIH may be helpful in differ- 3. Calcium regulated intracellular Protein Kinase C is entiating between it and increases in preexisting pain. likely a link between cellular mechanisms of toler- OIH will exacerbate a preexisting painful condition ance and OIH (16,18,19). and therefore will increase pain intensity above the 4. Cross talk of neural mechanisms of pain and toler- preexistent pain levels. However, further pro- ance may exist (20,21). gression needs to be ruled out which would increase 5. Prolonged morphine administration induces neu- pain. The practitioner must also consider additional rotoxicity via NMDA receptor mediated apoptotic increased pain resulting from increased activity or de- cell death in the dorsal horn (22). mand (often referred to as pseudotolerance). Further- more, OIH typically produces diffuse pain, less defined Role of Spinal Dynorphin in quality, which extends to other areas of distribution Spinal dynorphin plays an important role in OIH in from the preexisting pain. OIH is not unlike the pain that levels have shown increases with continuous infu- experienced during opioid withdrawal, since the neu- sions of mu receptor agonists. These increased levels robiology of both is similar (7). lead to the release of spinal excitatory neuropeptides OIH has been demonstrated clinically by inducing such as calcitonin gene-related peptide from primary changes in pain threshold, tolerability, and distribution afferents (23). OIH is therefore a pro-nociceptive pro- pattern in opioid-maintained former addicts (12). cess facilitated by increasing the synthesis of excitato- Finally, if the preexisting pain is undertreated or ry neuropeptides and their release upon peripheral if pharmacologic tolerance exists, then an increase in nocioceptive stimulation (7). opioid dose will result in reduction of pain. Conversely, OIH would be worsened with increasing opioid dose. Role of Descending Facilitation Opioid Induced Hyperalgesia Treatment Descending facilitation influence on OIH may be Strategies seen through several mechanisms. Subsets of neurons (on and off cells) within the rostral ventromedial medul- The pain practitioner has several options when la (RVM) have a unique response to opioids (24,25). Their confronted with a demonstrated lack of opioid efficacy. activities may facilitate spinal nocioceptive processing Rational polypharmacy to include non-opioid medica- (26). In addition, lesioning of the descending pathway tion should be utilized when treating any patient with to the spinal cord (dorsal lateral funiculus) prevents the intractable pain. This strategy helps minimize the dose increase seen in excitatory neuropeptides (23). of opioid used, thus reducing the possibility of side

www.painphysicianjournal.com 681 Pain Physician: May/June 2009: 12:679-684

effects and therefore, OIH. tends to contributing to OIH. Buprenorphine is a kappa recep- preferentially respond to non-opioid medications such tor antagonist. For these reasons, buprenorphine may as and . Rotation to a be unique in its ability to treat chronic pain and pos- different class of opioid may yield improvement in an- sibly OIH. algesia. Interventional can reduce Practical Considerations the need for pharmacotherapy altogether. Behavioral management can accomplish similar goals. The treatment of OIH can be time-consuming and However, if these options are not feasible, then at times, impractical. Weaning patients from high dose the practitioner is faced with several choices to diag- opioids usually requires time and patience (for both nose and treat OIH: the physician and patient). While reducing the opioid 1. Increase the dose of opioid and evaluate for in- dose, patients may experience transient increases in creased efficacy (tolerance). pain or mild withdrawal which can exacerbate pain. 2. Reduce or eliminate the opioid and evaluate The hyperalgesic effect may not be mitigated until a (OIH). certain critical dose of opioid is reached. Patients of- 3. Utilize opioids with unique properties that may ten become frustrated and managing the appropriate mitigate OIH. dose reductions often requires multiple office visits. 4. Utilize specific agents that are NMDA receptor This can be extremely impractical in a managed care antagonists. environment. In the author’s experience, many pa- The third option has become particularly attrac- tients simply give up and seek to resume opioid ther- tive with the use of and buprenorphine. apy elsewhere. Methadone, although a pure mu receptor agonist, has Breaking the cycle of pain and hyperalgesia (in properties that may prevent or reduce OIH (27). It is some cases opioid dependence and addiction) is an a racemic mixture in which the d-isomer is an NMDA attractive course of action for the interventional pain receptor antagonist. Methadone also displays incom- specialist. Interventional pain management seeks to plete cross-tolerance properties unique from other mu isolate or block pain input from specific nocicep- receptor agonists which may create a niche role for it tive points in the nervous system. This usually pro- in the treatment of OIH and other forms of intractable vides rapid diagnostic information and often results pain, especially neuropathic pain. Anecdotal reports in therapeutic improvement. Medically supervised exist of patients who have been thought to have OIH withdrawal with sublingual buprenorphine also pro- and been treated with combinations of option 2 and vides a rapid, safe, and effective treatment for opi- option 3 — i.e. reducing the dose of opioid (by 40 – oid dependence, thus breaking the cycle of pain and 50%) and adding “low-dose” methadone (28). hyperalgesia. Buprenorphine has been used to treat chronic Sublingual buprenorphine has recently been ap- pain (29). It is a partial opioid agonist with antago- proved for the treatment of opioid dependence and nist properties which has been used for decades in through its use, a physician can provide rapid and ef- and for the treatment of pain. The IV/IM ficient medically supervised withdrawal from opioids formulation (Buprenex) is available in the US for the in an office setting (31). Office-based detoxification treatment of pain and in Europe is available as a trans- is itself an “interventional medical technique” for dermal preparation. Most recently, it has been used the treatment of this complex patient population for the treatment of opioid dependence in its sublin- from pain, chemical dependency, and OIH. gual form (Suboxone, Subutex). Resolution of OIH usually follows quickly during the Buprenorphine has been shown to be intermedi- maintenance phase with buprenorphine. Office-based ate in its ability to induce pain sensitivity in patients detoxification provides a means to resolve OIH with- maintained on methadone and control patients not out the frustrations mentioned earlier. taking opioids (12). Buprenorphine showed an en- Methadone can be used to treat OIH. As stated hanced ability to treat hyperalgesia experimentally earlier, it may be more effective for treatment of induced in volunteers compared to fentanyl (30). In neuropathic pain. Converting a patient to metha- addition, spinal dynorphin, a known kappa receptor done offers a controlled method of weaning from agonist, increases during opioid administration, thus opioids. The pharmacologic rationale for the use of

682 www.painphysicianjournal.com Opioid Induced Hyperalgesia

methadone is its ability to relieve withdrawal. Since has also been shown to produce paradoxical pain methadone has a relatively long half-life (24 to 36 in rats (42). Since OIH and the pain hours), there are fewer variations in plasma levels from opioid withdrawal share many similarities (both compared to short acting opioids such as in quality and neurochemistry), it is conceivable that and . It is these properties which have clonidine may be useful in the treatment of OIH. made methadone the standard for the treatment of Conclusion opioid dependence in the U.S. for the past 4 decades (32,33). As long as methadone is not used to treat As with any therapy, side effects and complica- opioid dependence, any physician can use it for the tions can occur. An exit strategy should exist when treatment of pain, and subsequently OIH (34). How- utilizing opioids to treat chronic pain because of the ever, methadone itself can also cause OIH (35), which potential complications in managing these patients may also limit its role. such as opioid dependence, addiction, and abuse. OIH has been used to treat OIH and as an ad- is a less recognized side effect of chronic opioid ther- juvant to opioid therapy for the treatment of chronic apy. However, it is becoming more prevalent as the pain (33-39). It is an NMDA receptor antagonist and number of patients receiving opioids for chronic pain has known intrinsic analgesic properties. Clonidine is increases (43). OIH should be considered in the dif- an alpha 2 agonist and has been used for the treat- ferential when opioid therapy fails. Prior to institut- ment of neuropathic pain, post-operative pain, and ing treatment with opioids, OIH should be addressed severe cancer pain (39-41). It is also widely used to with patients as part of a comprehensive informed treat the symptoms of opioid withdrawal. Clonidine consent/agreement.

References 1. American Society of Addiction Medicine 8. Celerier E, Rivat C, Jun Y, Laulin JP, Larch- 14. Trujillo KA, Akil H. Inhibition of mor- (ASAM). Definitions Related to the Use er A, Reynier P, Simonnet G. Long-last- phine tolerance and dependence by the of Opioids for the Treatment of Pain: A ing hyperalgesia induced by fentanyl in NMDA receptor antagonist MK-801. Sci- Consensus Document from the Amer- rats: Preventive effect of ketamine. An- ence 1991; 251:85-87. ican Academy of Pain Medicine, the esthesiology 2000; 92:465-472. 15. Marek P, Ben Eliyahu S, Gold M, Liebe- American Pain Society, and the Amer- 9. Celerier E, Laulin JP, Corcuff JB, Le Moal skind JC. Excitatory amino acid antago- ican Society of Addiction Medicine. M, Simonnet G. Progressive enhance- nists (kynurenic acid and MK-801) atten- American Academy of Pain Medicine, ment of delayed hyperalgesia induced uate the development of morphine tol- Glenview, IL, 2001. by repeated heroin administration: A erance in the rat. Brain Research 1991; 2. Albutt C. On the abuse of hypoder- sensitization process. J Neurosci 2001; 547:77-81. mic injections of morphia. Practitioner 21:4074-4080. 16. Mao J, Price DD, Mayer DJ. Thermal hy- 1870; 5:327-331. 10. Guignard B, Bossard AE, Coste C, Ses- peralgesia in association with the de- 3. American Psychiatric Association. Diag- sler DI, Lebrault C, Alfonsi P, Fletcher velopment of morphine tolerance in nostic and Statistical Manual of Mental D, Chauvin M. opioid tolerance: rats: Roles of excitatory amino acid re- Disorders, 4th Edition (DSM-IV). Ameri- Intraoperative remifentanil increases ceptors and protein kinase C. J Neuro- can Psychiatric Press. Washington, DC, postoperative pain and morphine re- sci 1994; 14:2301-2312. 1994. quirement. Anesthesiology 2000; 93: 17. Mao J, Sung B, Ji RR, Lim G. Chronic mor- 4. American Society of Addiction, Princi- 409-417. phine induces downregulation of spinal ples of Addiction Medicine, 3rd edition, 11. Baron, MJ, McDonald PW. Significant glutamate transporters: Implications in Medicine, 2003, pp 3-16. pain reduction in chronic pain patients morphine tolerance and abnormal pain 5. Yaksh Tl, Malmberg AB. Central phar- after detoxification from high dose opi- sensitivity. J Neurosci 2002; 22:8312- macology of nociceptive transmission. oids. J Opioid Manag 2006; 2:277-282. 8323. In Wall P, Melzack (eds): Textbook of 12. Compton P, Charuvastra VC, Ling W. 18. Narita M, Mizoguchi H, Nagase H, Su- Pain, 3rd ed, 1994; pp. 165-200. Pain intolerance in opioid-maintained zuki T, Tseng LF. Involvement of spinal 6. Mao J. Opioid-induced abnormal pain former addicts: Effect of long- protein kinase C gamma in the atten- sensitivity: Implications in clinical opi- acting maintenance agent. Drug and Al- uation of opioid-mu-receptor mediat- oid therapy. Pain 2002; 100:213-217. cohol Dependence 2001; 63:139-146. ed G-protein activity after chronic in- 7. Mao J, Price D, Mayer D. Mechanisms of 13. Angst MS, Clark JD. Opioid-induced Hy- trathecal administration of [D-Ala2,N- hyperalgesia and morphine tolerance: peralgesia: A qualitative systematic re- Mephe4,Gly-Ol5] enkephalin. J Neurosci A current view of their possible interac- view. Anesthesiology 2006; 104:570- 2001; 21:3715-3720. tions. Pain 1995; 62:259-274. 587. 19. Zeitz KP, Malmberg AB, Gilbert H, Bas-

www.painphysicianjournal.com 683 Pain Physician: May/June 2009: 12:679-684

baum AI. Reduced development of tol- ceptive modulatory systems in periaq- Cochrane Database Systematic Review erance to the analgesic effects of mor- ueductal gray and spinal cord with ros- 2003; CD003351. phine and clonidine in PKC gamma mu- tral ventromedial medulla. Neurosci- 37. McQueen AL, Baroletti SA. Adjuvant tant mice. Pain 2002; 94:245-253. ence 1992; 47:863-871. ketamine analgesia for the manage- 20. Mao J. NMDA and opioid receptors: 27. Davis A, Inturrisi C. d-Methadone blocks ment of cancer pain. Annals Pharmaco- Their interactions in anti-, morphine tolerance and N-Methyl-D-as- therapy 2002; 36:1614-1619. tolerance and . Brain partate-induced. The Journal of Phar- 38. Mercadante S, Villari P, Ferrera P. Burst Res Rev 1999; 30:289-304. macology and Experimental Therapeu- ketamine to reverse opioid tolerance in tics 1999; 289:1048-1053. 21. Mao J, Price DD, Mayer DJ. Experimen- cancer pain. Journal of Pain and Symp- tal mononeuropathy reduces the anti- 28. Vorobeychik Y, Chen L, Bush MC, Mao tom Management 2003; 25:302-305. nociceptive effects of morphine: Impli- J. Improved opioid analgesic effect fol- 39. Kingery WS. A critical review of con- cations for common intracellular mech- lowing opioid dose reduction. Pain Med trolled clinical trials for peripheral neu- anisms involved in morphine toler- 2008; 9:724-727. ropathic pain and complex regional pain ance and neuropathic pain. Pain 1995; 29. Johnson RE, Fudala PJ, Payne R. Bu- syndromes. Pain 1997; 73:123-139. 61:353-364. prenorphine: Considerations for pain 40. Sites BD, Beach M, Biggs R, Rohan C, 22. Mao J, Sung B, Ru-Rong J, Grewo L. management. J Pain Symptom Man- Wiley C, Rassias A. Gregory J, Fanciullo Neuronal apoptosis associated with ag2005; 29:297-326. G. Intrathecal clonidine added to a bu- morphine tolerance: Evidence for an 30. Koppert W, Ihmsen H, Korber N, Wehr- pivacaine-morphine spinal anesthetic opioid-induced neurotoxic mechanism. fritz A, Sittl R, Schmelz M. Different pro- improves postoperative analgesia for J Neurosci 2002; 22:7650-7661. files of buprenorphine induced anal- total knee arthroplasty. Anesth Analg 23. Gardell LR, Wang R, Burgess SE, Ossi- gesia and antihyperalgesia in a human 2003; 96:1083-1088. pov MH, Vanderah TW, Malan Jr. TP, Lai pain model. Pain 2005; 118:15-22. 41. Tumber PS, Fitzgibbon DR. The control J, Porreca F. Sustained morphine expo- 31. Helm S, Trescot A, Colson J, Sehgal N, of severe cancer pain by continuous sure induces a spinal dynorphin-de- Silverman S. Opioid antagonists, partial intrathecal infusion and patient con- pendent enhancement of excitatory agonists, and agonists/antagonists: trolled intrathecal analgesia with mor- transmitter release form primary affer- The role of office-based detoxification. phine, bupivacaine and clonidine. Pain ent fibers. J Neurosci 2002; 22:6747- Pain Physician 2008; 11:225-235. 1998; 78:217-220. 6755. 32. Dole VP, Narcotic addiction, physical 42. Quartilho A, Mata HP, Ibrahim MM, Van- 24. Barbaro NM, Heinricher MM, Fields HL. dependence and relapse. N Engl J Med derah TW, Ossipov MH, Lai J, Porreca F, Putative pain modulating neurons in 1972; 286:988-992. Malan TP Jr. Production of paradoxical the rostral ventral medulla: Reflex-re- 33. Kosten TR, Current pharmacotherapies sensory hypersensitivity by alpha2-ad- lated activity predicts effects of mor- for opioid dependence. Psychopharma- renoreceptor agonist. Anesthesiology phine. Brain Research 1986; 366:203- cology Bulletin 1990; 26:69-74. 2004; 100:1538-1544. 210. 34. Heit HA, Covington E, Good PA. Dear 43. Trescot AM, Helm S, Hansen H, Be- 25. Heinricher MM, Morgan MM, Fields DEA. Pain Med 2004; 5:303-308. nyamin R, Glaser SE, Adlaka R, Patel HL. Direct and indirect actions of mor- 35. Davis MP, Shaiova LA, Angst M. When S, Manchikanti L. Opioids in the man- phine on medullary neurons that mod- opioids cause pain. Journal of Clinical agement of chronic non-cancer pain: ulate nociception. Neuroscience 1992; Oncology 2007; 25:4497-4498. An update of American Society of the 48:533-543. Interventional Pain (ASIPP) 36. Bell R, Eccleston C, Kalso E. Ketamine as Guidelines. Pain Physician 2008; 11: 26. Morgan MM, Heinricher MM, Fields HL. an adjuvant to opioids for cancer pain. Circuitry linking opioid-sensitive noci- S12-S16.

684 www.painphysicianjournal.com