Disclosures: These presenters have no financial relationships with commercial interests.

Transcription

1 Session: L146 Session: L318 Back Pain in the Painful Patient: Opioid Abuse, Buprenorphine, and Now the Operating Room! Geeta Nagpal, M.D., Vincent M. Tupper, M.D. Northwestern University, Chicago, IL Disclosures: These presenters have no financial relationships with commercial interests. Stem Case and Key Questions Content A 42-year-old man is referred to your pain clinic for evaluation of chronic low back pain. He comes from the local county care clinic and the referring provider asks for "medication and injection management." The patient has been in pain for 20 years, and his main concern is pain in the low back that radiates into the right lateral thigh, leg and into the foot. He is currently taking hydrocodone/acetaminophen 10/325 mg 6 times daily for the pain. He has used his last tab yesterday was told he would get his refill today at this appointment by his primary care doctor. What are the best treatment options for this patient? What medications would you choose? Are there interventional approaches that are appropriate? Are there tests that should be ordered? During the evaluation, he denies any past medical or surgical history. He states he has only ever had hydrocodone/acetaminophen or oxycodone for pain control and has never had any interventional management. Upon examining the patient in the clinic, he is noted to have severe scoliosis, right tibialis anterior and extensor hallucis longus weakness at 4/5, but intact reflexes and sensation. His lumbar MRI (magnetic resonance imaging) confirms the scoliosis and reveals degenerative disk disease (DDD), worst at L5-S1 with neuroforaminal narrowing on the right. You note a small piece of tissue soaked with heme on his left lateral neck. He states this is where he recently injected heroin. Are there any interventional approaches to this patient's pain that can be considered? Are additional tests necessary? Is it OK to do an epidural steroid injection in an active drug user? Are the risk factors for intravenous drug use different than oral or intranasal? Can you obtain informed consent? You decide against epidural steroid injection and explain your decision to the patient. You state under the influence of heroin, you are unable to do proper informed consent. He asks for his refill of hydrocodone, explaining that the only reason he does heroin is because he has uncontrolled pain. He is motivated to quit, but feels he cannot because of the level of pain that has consumed years of his life. Is it reasonable to give him a prescription for opioids? Are there any other medications to recommend Page 1

2 or prescribe? Would doing an injection be a safer option for pain control? What other options are there? Because the patient seems motivated, you give him a referral to a drug and alcohol treatment facility. He voices concern over methadone maintenance as he has heard there can be horrible side effects and reiterates that he prefers hydrocodone. He states he only used heroin because he ran out of the previous prescription and it is cheaper than pills off the street. Are there other options for the treatment of addiction? What if the patient did not seem motivated? Would it be reasonable to write prescriptions for opioids monthly with urine drug screens? How long is heroin detectable? Are you responsible to call the authorities? Six months later, he returns to your office and has been scheduled for a lumbar epidural steroid injection. In the interim, he spent time in jail for burglary and was put on buprenorphine/naloxone sublingual treatment for his addiction. He states he continues to have extraordinary low back pain and right lower extremity radiating symptoms. He has been clean of illicit substances for ten weeks and would like to proceed with injection therapy. He was told he could have sedation with the procedure as long as he had nothing by mouth for 6 hours prior. He insists he will need strong pain medication to be able to tolerate the procedure. Is it OK to do the procedure while taking buprenorphine? Should you postpone the procedure until he can hold the medication for one day? Three days? Should he have a urine drug screen prior? Can you give sedation while on this treatment? Will it work? A right paramedian L5-S1 epidural steroid injection is done without event. He is transferred to the recovery bay and monitored for thirty minutes. At discharge he complains of increasing pain in the low back and right leg and asks for hydrocodone or oxycodone. He states he cannot walk and cannot be discharged in the amount of pain he has. His strength exam is unchanged from the initial visit as well as reflexes and sensation. Why would he be having more pain? Will you give more pain medication in the IV? Are there medications to prescribe? Is there concern that warrants further tests? Should he be sent to the Emergency Department? Four days later, the patient presents to the Emergency Department (ED) after a fall at home. He was unable to stand back up and had to call for assistance. He states he has low back pain that is worse than baseline and he feels like he has pain into both legs now. His physical exam is unchanged, and his vital sign are 112/72, 111, 101.1, 98% RA. The ED physician calls you for help with pain management. Page 2

3 What treatment would you recommend? Are there any concerns about the pain or the new bilateral symptoms? Is further testing necessary? Would you ask for labs or imaging? A complete blood count reveals a white blood cell count of 11, platelets of 75,000, and an elevated C- reactive protein. An MRI of the lumbar spine is done which shows an epidural abscess extending from L2-T10. Neurosurgery determines that emergency decompression and laminectomy is required. The patient is complaining that his pain is not being well controlled. What type of intraoperative management of this patient's pain would be best? What medications would you choose? Are there infusions that would be helpful? Can these medications be given perioperatively? You decide to give IV bolus doses of methadone and run a ketamine infusion at 0.3mg/kg/hour during the case. The operation goes uneventfully and the patient remains hemodynamically stable throughout. The patient goes to the post anesthesia care unit with the ketamine infusion. Fifteen minutes later, you are called by the nurse and informed that his heart rate is 130 and he is complaining of pain. Is his tachycardia a result of pain? Should you increase the ketamine infusion? More methadone? Should you try a different medication? Is there concern for opioid induced hyperaglesia? After boluses of IV fentanyl and an increase in the ketamine infusion to 0.5mg/kg/hour, the patient is transferred to the floor. He continues to have a level 6/10 pain, but is visibly more comfortable. The ketamine infusion is weaned and he is started on oral methadone 20mg three times daily with a fentanyl PCA (patient controlled analgesia) for break through pain. He asks the nurse for his morning daily dose of buprenorphine. When should the buprenorphine be restarted? How will you discharge the patient from the hospital with treatment for the pain and addiction? Is it safe to prescribe a recovering opioid addict short-acting agents? Model Discussion Content Introduction Chronic pain is defined as pain that is persistent and lasting more than 3 to 6 months. Nearly one third of the American population has experienced or is living in chronic pain. Of this, chronic low back pain is the most prevalent, in 1998 costing nearly $100 billion in direct health care expenditure.1 Over the last several decades, there has been a dramatic increase in the development of opioid medications for the treatment of pain. With this increase, we have seen the yearly prescriptions of opioids catapult Page 3

4 from 76 million to 203 million over a 20-year period.2 Unfortunately, this increase in dispensing is directly correlated with an increase in opioid abuse. 3 As this number of addicted persons increases, so do the numbers of those in recovery from opioid addiction. Often these patients are on opioid maintenance therapy, designed to reduce cravings and the euphoric effects. While methadone maintenance was the treatment option of choice for many years, it required quite intensive monitoring and observational programs. It was in 2000 that the Drug Addiction Treatment Act passed, and now physicians could legally prescribe opioids (buprenorphine) for the treatment of opioid addiction. 4 Two years following this, the U.S. Food and Drug Administration (FDA) approved buprenorphine/naloxone for treatment of opioid dependence. 4 After its popularization for the treatment of addiction and dependence, the off-label use of buprenorphine commenced for the treatment of chronic pain. While buprenorphine/naloxone is effective in preventing the euphoria if opioids are abused, they also interfere with the use of other opioids in the treatment of legitimate pain, notably in the perioperative setting. Because of this, this medication presents unique challenges in the treatment of acute pain to the anesthesiologist in the perioperative setting. Opioid Substitution Therapy (OST) Long-term approaches to the treatment of opioid addiction are required because of opioid's persistent alterations on the dopaminergic, opioidergic, and stress responsive pathways. In addition to psychosocial interventions, methadone and buprenorphinenaloxone have been utilized to prevent withdrawal symptoms and serve as opioid replacements. Methadone is a synthetic mu opioid receptor agonist, NMDA (N-methyl-D-asparate) receptor antagonist, and a serotonin/norepinephrine reuptake inhibitor. It has an excellent oral bioavailability of 70-80% and an approximate 22-hour half-life (ranging from 15 to 60 hours).5 Methadone has been plagued with misconceptions about its onset of action and duration of analgesia, leaving it relatively invisible in the operating room setting. However, it does have a relatively fast onset, as it can equilibrate in the plasma and central nervous system in 4 and 8 minutes respectively, which is comparable to fentanyl and sufentanil. 6 Buprenorphine is a semi-synthetic mu opioid partial agonist that has several mechanisms of action that account for its unique characteristics. Buprenorphine serves as a competitive inhibitor to other opioids due to its high mu receptor binding affinity. It also acts as a partial mu opioid receptor agonist. Its potency is 25 to 50-fold higher than that of morphine, but the agonist effects are much lower.4 In addition, it dissociates from the receptors incredibly slowly. For example, while fentanyl has a dissociation half-time of 7 minutes, buprenorphine is about 25 times slower with a dissociation half-time of 166 minutes. 4 Lastly, it acts as an antagonist at the kappa opioid receptors. 3 The kappa opioid receptor is responsible for the dysphoric and psychotomimetic effects, and the use of buprenorphine can diminish these. Buprenorphine's partial agonism prevents opioid withdrawal symptoms, but also causes a ceiling effect therapeutically. 7 Metabolically, it has a poor oral bioavailability, however, sublingually the bioavailability is 40% with a 37-hour elimination half-life. These properties enable a once a daily dosing, which is ideal for OST. 3 Buprenorphine possesses a ceiling effect on euphoria around 16 mg (stabilizing dose is 12-16mg), thereby discouraging dose escalation abuse. To counteract abuse potential buprenorphine was formulated Page 4

5 with naloxone, a short acting competitive opioid receptor antagonist. The exact formulation of buprenorphine-naloxone is 4:1, which capitalizes on the pharmacokinetics of each drug. First, buprenorphine has a duration of action 10 times longer than naloxone (966 minutes versus 105 minutes), which limits the extent of opioid reversal. Secondly, sublingually naloxone has a bioavailability of approximately 10% vs. buprenorphine's 40%, thereby diminishing or even eliminating naloxone's antagonistic effects. If buprenorphine/naloxone is injected, the naloxone effect is greatly enhanced and will limit the reward perception of buprenorphine. This makes the drug undesirable to intravenous injection as a form of abuse. 3 Buprenorphine/naloxone for pain management Patients with chronic pain and a current or past history of substance abuse can be some of the most difficult to manage. Numerous issues including tolerance to multiple opioids, opioid induced hyperalgesia, and aberrant drug behaviors can complicate treatment in this population. There are multiple characteristics of buprenorphine/naloxone that make it a reasonable option for the treatment of pain, and not just addiction. The low addictive potential and the partial agonism of the mu-opioid receptor certainly play a role. There are studies that support the use of buprenorphine/naloxone in the treatment of chronic pain in opioid-dependent patients. Daitch et al. did a retrospective study of 104 patients that had poorly controlled pain despite current opioid therapy. Within 60-days of conversion from full agonist to buprenorphine/naloxone, there was an average of 2.3 reduction in pain on a 0-10 scale.8 Roux et al. did a randominzed control trial comparing 2, 8, and 16mg buprenorphine in random order to replace patient's chronic pre-treatment opioids. Patients could then self-administer oxycodone at varying doses orally as needed for pain. They found that buprenorphine/naloxone reduced both pain and withdrawal symptoms as well as abuse of the oxycodone.9 Interestingly, the effectiveness of buprenorphine/naloxone or buprenorphine alone for the treatment of chronic pain in the non-opioid dependent patient is not as clear.3 The same reasons that make it a good option for addiction, make it suboptimal for the treatment of pain in the opioid-naïve patient. It is a weak analgesic and only partially activates the mu-opioid receptor, reaching its ceiling effect at moderate doses. And in higher doses, it will act as an opioid antagonist, only adding to its ineffectiveness. Buprenorphine/naloxone in the surgical setting Currently, there is little data regarding the impact of buprenorphine therapy on anesthesia. Most of the recommendations are based upon case reports and shared experiences of successful treatments of these patients. There are multiple ways to prepare for a patient on opioid substitution therapy (OST)for the perioperative period. For the elective case, the most common and preferred method is to discontinue the drug prior to surgery. This can be done gradually over a few weeks period with reductions in dosage by 2mg every 2-3 days with complete discontinuation 3 days prior to surgery. If pain control or cravings are a problem, the buprenorphine can be transitioned to another long acting opioid 3-7 days prior to the planned surgery. In addition to this method, there are also reports of maintaining the maintenance dose with the addition of short-acting opioids or simply increasing the total daily dose of buprenorphine and splitting it into three times daily dosing. The prediction of the postoperative pain severity certainly plays a large role in this decision. Page 5

6 Options for the elective surgical procedure: 7 1. Transition to methadone 30-40mg per day. If there are signs of opioid withdrawal, increase methadone 5-10mg per day. Once the acute pain of the procedure has resolved, return to preoperative OST. Caution must be taken at this stage for if the patient is on higher dose opioids, the reintroduction of buprenorphine could precipitate withdrawal symptoms. 2. Use the maintenance dose of buprenorphine over the 24 hours period with dosing every 6-8 hours. This method relies on the analgesic effect of the drug, which is reasonable only for mild to moderate pain. The addition of a short-acting opioid such as fentanyl should be used as needed, understanding that higher than typical doses will be necessary. 3. If you are able to stop the buprenorphine completely, it should be done at least 72 hours prior to surgery. At this point, the standard opioids used for analgesia will be effective. If the patient has uncomfortable withdrawal symptoms or they are at risk for relapse during this time, please refer to number 1. 7 In an emergency situation, as with our patient, the options are to continue usage versus complete discontinuation. The elimination half-life of buprenorphine ranges from hours10 so caution is advised as high opioid dose requirements in the initial few days could cause respiratory depression once the buprenorphine dissociates from the mu receptor and is eliminated. In a case report described by McCormick et al., a patient treated with buprenorphine/naloxone for chronic pain presented to the Emergency Department with bilateral anterior thigh compartment syndrome. His buprenorphine was held and he received 12mg intravenous hydromorphone over 8 hours with no relief of the pain. He was taken for emergency fasciotomy and postoperatively was on hydromorphone 0.5 mg/hr basal with 0.8mg as needed with 15-minute lockout. It was not until postoperative day 2 that the patient's pain was under control and he was discharged on alternative oral agents. His buprenorphine was restarted 2 months after discharge.11 Opioid Induced Hyperalgesia in the Perioperative Setting Opioid induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. In such cases, when opioids are given with the intention of eliminating pain, there can be an unexpectedly heightened sensation of pain, caused by a lowering of the pain threshold. Because most patients with OIH in the perioperative period have a history of chronic opioid use, it may be mistaken for tolerance. However, they are different phenomena: increasing opioid dose aggravates OIH whereas in tolerance, it does not. OIH is characterized by increased pain sensitivity and involves sensitization of the pronociceptive pathways while tolerance is characterized by a loss of drug potency, likely by desensitization of the antinociceptive pathways to opioids.12 Multiple mechanisms for OIH have been proposed and have been attributed to the central glutaminergic system, spinal dynorphins, and descending facilitation, all of which may play a role in Page 6

7 producing a pronociceptive state.13 Mao et al. proposed that an increase in responsiveness of the N- Methyl-D-aspartate (NMDA) receptors contribute to the development of OIH, supported by a finding that an NMDA antagonist prevented the development of OIH in rats.14 Consequently, clinical work in preventing OIH has primarily focused on manipulation of the glutaminergic system, either through direct or indirect modulation of the NMDA receptor.15 In the case of rapid opioid dose escalation and continued pain, the development of hyperalgesia should be suspected and alternative therapies should be considered including NMDA receptor antagonists, cyclooxygenase (COX) inhibitors, and alpha 2-receptor agonists.12 Ketamine has been shown to be greatly beneficial in patients who require large amounts of opioids or exhibit some degree of opioid tolerance.15 There is some evidence to show that the perioperative administration of low dose ketamine (0.2mg/kg/hr) might modulate the expression of OIH and that it reduces postoperative wound hyperalgesia.16 Methadone has also been shown to have weak NMDA receptor antagonism and has also been effective in reducing high-dose OIH. However, it has multiple disadvantages with a complex conversion, extended half-life, and Q-T prolongation. It may not be as easily usable in the postoperative setting for this patient as compared to ketamine. Prostaglandins can stimulate glutamate release in the spinal cord resulting in activation of NMDA receptors. Therefore, COX inhibitors would antagonize this NMDA activation and further inhibit OIH.12 They have been shown to attenuate the development of opioid tolerance in animals.15 The use of ketorolac or celecoxib could be beneficial for decreasing opioid requirement as well as OIH. The alpha 2-receptor agonists have also been examined in modulating OIH. Koppert et al showed that in healthy volunteers, clonidine administered with a remifentanil infusion abolished opioid-induced post-infusion secondary hyperalgesia.17 The data does suggest that clonidine could have a potential role for OIH modulation. While there are several options when confronted with the lack of opioid efficacy and the diagnosis of OIH is made, the treatment can be quite time-consuming and costly. In many institutions, the use of a ketamine infusion requires a high level of monitoring in a post anesthesia care unit (PACU) or intensive care unit (ICU). The use of other adjuvant drugs as described above may be useful in reducing the need for opioid escalation and minimizing the opioid dosage, thereby treating opioid induced hyperalgesia. Conclusions Prescription opioid abuse has grown to epidemic proportions in the United States, correlating with a dramatic increase in the prescription of medications such as Oxycontin, Percocet and Vicodin. In 2002, the U.S. FDA approved buprenorphine/naloxone for the treatment of opioid dependence. Since then, there has been a growing population of patients with chronic pain complicated by dependence and addiction on this treatment. Managing an opioid dependent patient is often a dynamic and complex task complicated by tolerance to multiple opioids and OIH. It is critical that providers both understand the intraoperative implications and are capable of adapting with a variety of adjuvant Page 7

8 therapies. In summary, if a patient is on methadone preoperatively, it should be continued throughout the postoperative period and providers should be in contact with a patient's dosing center. It is not uncommon that a patient's methadone requirement will increase after surgery, but this adjustment should be made with communication with the patient's prescribing physician. Unlike methadone, buprenorphine-naloxone ideally should be held until the patient is out of the acute perioperative period. From case reports and personal experience, we know that continued buprenorphine-naloxone creates the need for tremendous opioid supplementation and potential inadequate pain control. In these cases, adjuvants such as regional blocks, neuraxial anesthesia, ketamine infusions, or simply acetaminophen and non-steroidal anti-inflammatories should be used. References 1 Bottros M, Cohen SP. Lumbar Discogenic Pain and Discography. Practical Management of Pain (65): e5 2 Volkow N. America's Addiction to Opioids: Heroin and Prescription Drug Abuse. The National Institue on Drug Abuse: Senate Caucus on International Narcotics Control. 2014, May Chen KY, Chen L, and Mao J, Buprenorphine-naloxone therapy in pain management. Anesthesiology May; 120(5): Bryson EO, Lipson S, Gervitz C. "Anesthesia for patients on buprenorphine." Anesthesiology Clin 28 (2010) Gottschalk A, Durieux M, Nemergut E. "Intraoperative methadone improves pain control in patients undergoing complex spine surgery." Anesth Analg Jan;112(1): Karashch ED. "Intraoperative methadone: rediscovery, reappraisal, and reinvigoration?" Anesth Analg Jan;112(1): Bryson EO. "The perioperative management of patients maintained on medications used to manage opioid addiction." Curr Opin Anesthesiol 2014, 27: Daitch J, Frey ME, Silver D, Mitnick C, Daitch D, Pergolizzi J Jr. "Conversion of chronic pain patients from full-opioid agonists to sublingual buprenorphine. Pain Physician 2012; 15(3 suppl):es Roux P, Sullivan MA, Cohen J, Fugon L, Jones JD, Vosburg SK, Cooper ZD, Manubay JM, Mogali S, Comer SD. "Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: Reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone. Pain 2013; 154: Accessed February 13, McCormick Z, Chu S, Chang-Chien G, Joseph P. "Acute pain control challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle's Disease: A case report and review." Pain Medicine 2013; 14: Lee H, Yeomans D. Opioid induced hyperalgesia in anesthetic settings. Korean J Anesthesiol Nov; 67 (5): Page 8

9 13 Merandante S. Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep (2014) 18: Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995 Sep; 62(3): Lee M, Silverman S, Hansen H, Patel V, Manchikanti L. A comprehensive review of opioid induced hyperalgesia. Pain Physician 2011; 14: Barreveld A, Correll D, Liu X, Max B, McGowan JA, Wasan AD, Nedeljkovic SS. Ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: results of a prospective, randomized, double-blind study. Pain Med Jun; 14(6): Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology Jul;99(1): Page 9