Eastern States Residency Conference

Eastern States Residency Conference
Strategies for Acute Pain Management in Patients on Extended-Release Naltrexone Megan T. Mitchell, PharmD PGY1 Pharmacy Resident UConn John Dempsey Hospital May 8th, 2018 Eastern States Residency Conference

Disclosure I have no conflict of interest to report
I intend to reference unlabeled/unapproved uses of drugs or products in my presentation

Learning Objectives List the FDA-approved indications for the use of extended-release naltrexone Identify appropriate non-opioid analgesic treatment options beyond the standard of care, for the management of severe, acute pain in patients on extended-release naltrexone injectable suspension

Extended-Release Naltrexone (ERN)
Once monthly intramuscular injection Indications Treatment of alcohol dependence Treatment of opioid dependence following detoxification Opioid antagonist Highest affinity for the mu opioid receptor Brand name – Vivitrol mg IM injection once every 4 weeks Injection lasts approximately 4 weeks, half life approximately 5-10 days Some cases have reported shorter durations of action than 4 weeks, seems to be patient dependent IM injection has a biphasic peaks (at ~2hrs and again at 2-3 days) Should be used as part of a comprehensive management strategy that includes psychosocial support Occupation of the opioid receptors by ERN will competitively and completely block the effects of exogenous opioids Extended Release Naltrexone Injectable Solution [package Insert]. Waltham, MA: Alkermes, Inc. 2015

Pharmacokinetics of ERN
Duration of action of ERN is approximately 28 days Important to assess the time of last injection The blockade is surmountable with high dose opiates Increased risk of respiratory depression and death I would imagine you may get some questions on the second bullet point here along the lines of “If a provider/patient was insistent on giving an opioid based on this, how would you go about that?” So in your discussion, I might address that (but maybe that is already in your plan) Extended Release Naltrexone Injectable Solution [package Insert]. Waltham, MA: Alkermes, Inc. 2015

Challenges of using ERN
Patient education is essential Patients should be highly self-motivated Risk of overdose if using higher doses than before Willingness to communicate to other providers Adherence to once monthly injection schedule Provider education

Challenges of using ERN
Currently no universal method for identifying these patients Altered mental status or unconscious Not dispensed through retail pharmacy Not reported on PMP Access to EMR is often limited Stigma related to use Highly encourage patients to utilize medical alert bracelets/tags

Elective Procedures Appropriate communication between healthcare professionals is key Track dates of administration Schedule elective procedures to fall as close to day 28 as possible Opioids can be used for acute post-op pain

Standard of Care for Managing Acute Pain
These non-opioid agents should be and are typically utilized as necessary for a wide range of pain - depending on the degree or severity of pain/injury for patients Regardless of whether or not they are being treated with extended release naltrexone They should be utilized based on confounding factors, nature of pain, drug interactions, allergies, etc… They can be very effective alone or in combination in treating many injuries BUT what do we do when these standard of care measures are not adequate

Standard of Care Acetaminophen NSAIDs Skeletal muscle relaxants
Baclofen, cyclobenzaprine, tizanidine Anticonvulsants Gabapentin, pregabalin Benzodiazepines Diazepam, midazolam, lorazepam, alprazolam

Clinical Question What strategies are available to treat severe, acute pain if these standard of care methods are not providing adequate relief and opioids are not an option? Often physicians can be flustered by the idea of having to treat severe pain and not being able to use opioids as an option. It is very likely that as the ‘drug expert’ that the MD/team may look to you and expect that you can create a pain management plan that will effectively manage the patients pain. With the prevalence of this drug increasing in our society, it is likely you will encounter this issue in clinical practice

Ketamine A non-competitive NMDA and glutamate receptor antagonist with potent analgesic, anxiolytic and amnestic properties Rapid onset of action Preserves airway patency, ventilation and cardiovascular stability Ketamine available as solution for IM or IV injection at concentrations of either 50 or 100 mg/ml Rapid onset of action given high lipophillicity and readily able to cross the BBB Ketamine has a wide margin of safety compared to opioids; several instances of unintentional administration of overdoses of ketamine (up to ten times that usually required) have been followed by prolonged but complete recovery. Contraindications: in those in whom a significant elevation of blood pressure would constitute a serious hazard and in those who have shown hypersensitivity to the drug. **From package insert 1. White PF, Way WL, & Trevor AJ: Ketamine - its pharmacology and therapeutic uses. Anesthesiology 1982; 56: 2. Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

Ketamine Anesthetic dosing Sub-dissociative dosing
mg/kg bolus 0.5 mg/kg/min Sub-dissociative dosing mg/kg bolus mg/kg/hr continuous infusion Titration based on pain control and signs of CNS/CV side effects FOR ANESTHESIA: The initial dose of ketamine administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to produce five to ten minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb). Alternatively, in adult patients an induction dose of 1 mg to 2 mg/kg intravenous ketamine at a rate of 0.5 mg/kg/min may be used for induction of anesthesia. DISSOCIATIVE EFFECTS: Ketamine is considered a dissociative anesthetic (other examples of this drug are PCP and DXM). This means that the drug distorts the users perception of sight and sound and produces feelings of detachment from the environment and ones self… Along with anesthetic benefits, there are certain reactions to ketamine that make it appealing to illicit users. In some circumstances, ketamine has been known to produce illusions or hallucinations that are enhanced by environmental stimuli - this may be one reason that the drug has become increasingly popular in the past few years. Other drugs that produce dissociative effects are PCP and DXM Pharmacodynamics: Involves analgesia, anesthetic and sympathomimetic effects that are mediated by different sites of action. Non-competitive NMDA receptor antagonism is associated with the analgesic effects; opiate receptors may contribute to analgesia and dysphoric reactions; and sympathomimetic properties may result from enhanced central and peripheral monoaminergic transmission. Ketamine blocks dopamine uptake and therefore elevates synaptic dopamine levels. Inhibition of central and peripheral cholinergic transmission could contribute to induction of the anesthetic state and hallucinations. Ketamine is structurally similar to PCP, but times less potent in blocking NMDA effects. Pharmacokinetics: Bioavailability following an intramuscular dose is 93%, intranasal dose 25-50%, and oral dose 20±7%. Ketamine is rapidly distributed into brain and other highly perfused tissues, and is 12% bound in plasma. The plasma half-life is 2.3 ± 0.5 hours. Oral administration produces lower peak concentrations of ketamine, but increased amounts of the metabolites norketamine and dehydronorketamine. Ketamine and its metabolites undergo hydroxylation and conjugation. Norketamine produces effects similar to those of ketamine. There are no significant differences between the pharmacokinetic properties of the S-(+) and R-(-)-isomers. CNS: depression, hypertonia (tonic clonic), and increased cerebrospinal fluid pressure CV side effects include: bradycardia, cardiac arrhythmia, hypotension, increased blood pressure, increased pulse Method This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years and experiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric rating scale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes. Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesia at 30 and 60 minutes Results Forty-five patients per group were enrolled in the study. The primary change in mean pain scores was not significantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95% confidence interval −0.46 to 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% confidence interval −1.19 to 1.46; P=.97). There was no difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes. No statistically significant or clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. Patients in the ketamine group reported increased minor adverse effects at 15 minutes post–drug administration. Conclusion Subdissociative IV ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of IV morphine for short-term treatment of acute pain in the ED. Continuous subQ infusion of ketamine was more effective than intermittent morphine in the treatment of pain associated with acute musculoskeletal injury in a double-blind study (N=40). The ketamine-treated group was given a loading dose of 0.25 mg/kg followed by 0.1 mg/kg/hr, and the morphine-treated patients were given 0.1 mg/kg IV every 4 hours. Supplementary analgesia was required by significantly more morphine-treated patients compared with ketamine group (18 vs 0). Ketamine patients were significantly more awake and alert, and they had significantly more improvement in peak expiratory flow rate than the morphine patients. There was a higher incidence of nausea and vomiting in the morphine group Gurnani A, Sharma PK, Rautela RS, et al: Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of ketamine. Anaesth Intensive Care 1996; 24:32-36 White PF, Way WL, & Trevor AJ: Ketamine - its pharmacology and therapeutic uses. Anesthesiology 1982; 56: Gurnani A, Sharma PK, Rautela RS, et al: Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of ketamine. Anaesth Intensive Care 1996; 24:32-36 Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

Dissociation and Emergence
Dissociation: patient passes into a trance like state At the doses used for pain, this side effect is less common Emergence: gradual return of consciousness after discontinuing administration of an anesthetic May be accompanied by psychotomimetic effects Perumal DK, Adhimoolam M, Selvaraj N, Lazarus SP, Mohammed MAR. Midazolam premedication for Ketamine-induced emergence phenomenon: A prospective observational study. Journal of Research in Pharmacy Practice. 2015;4(2):89-93. LOHIT K, SRINIVAS V, CHANDA KULKARNI, SHAHEEN. A CLINICAL EVALUATION OF THE EFFECTS OF ADMINISTRATION OF MIDAZOLAM ON KETAMINE- INDUCED EMERGENCE PHENOMENON. Journal of Clinical and Diagnostic Research [serial online] 2011 April [cited: 2018 Jan 15 ]; 5: DISSOCIATIVE EFFECTS: Ketamine is considered a dissociative anesthetic (other examples of this drug are PCP and DXM). This means that the drug distorts the users perception of sight and sound and produces feelings of detachment from the environment and ones self… Along with anesthetic benefits, there are certain reactions to ketamine that make it appealing to illicit users. In some circumstances, ketamine has been known to produce illusions or hallucinations that are enhanced by environmental stimuli - this may be one reason that the drug has become increasingly popular in the past few years. Other drugs that produce dissociative effects are PCP and DXM Emergence is the gradual return of consciousness after discontinuing administration of anesthetic and adjuvant agents at the end of a surgical procedure. Most patients transition smoothly from a surgical anesthetic state to an awake state with intact protective reflexes (STAGE 1). After emergence in the operating room, transport to the PACU is typically accomplished when the patient has been extubated and is breathing spontaneously with adequate oxygenation and ventilation, is hemodynamically stable, and can be aroused to follow simple verbal commands. Most patients become fully conscious within approximately 15 minutes of extubation and all patients should be responsive within 60 minutes after the last administration of any sedative, opioid or anesthetic agent. Emergence delirium may present in two ways (hyperactive and hypoactive subtypes) There is some literature to suggest that pre-treating or co-treatment with midazolam may reduce the risk of this phenomenon post ketamine administration, however the literature is minimal and there are conflicting reports If there is concern for dissociation/emergence, start at the lowest end of the dosing and titrate up very slowly to adequate pain control Ketamine use in the elderly and controversial given already increased risk of delirium – is there any evidence to support its use?? Perumal DK, Adhimoolam M, Selvaraj N, Lazarus SP, Mohammed MAR. Midazolam premedication for Ketamine-induced emergence phenomenon: A prospective observational study. Journal of Research in Pharmacy Practice. 2015;4(2):89-93.

Ketamine Risks to consider Increased BP and HR Respiratory depression
Following rapid IV pushes of high doses Diplopia or nystagmus Slightly elevated intraocular pressure Enhanced skeletal muscle tone Manifested by tonic-clonic movements Works quickly because lipophilic and crosses BBB – structurally similar to PCP Cardiovascular Blood pressure and pulse rate are frequently elevated following administration of ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia has also occurred. Respiration Although respiration is frequently stimulated, and airway patency is preserved… severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine. Laryngospasms and other forms of airway obstruction have occurred during ketamine anesthesia. Eye Diplopia and nystagmus have been noted following ketamine administration. It also may cause a slight elevation in intraocular pressure measurement. Genitourinary Severe irritative and inflammatory urinary tract and bladder symptoms including cystitis have been reported in individuals with history of chronic ketamine use or abuse. Neurological In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures Gastrointestinal Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness General: Anaphylaxis; Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have also been reported and its important to know upon initiation of the drug Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

Peripheral Nerve Blocks (PNB)
Continuous PNB vs. Single shot PNB Used for localized injuries Performed by injection of the anesthetic adjacent to a nerve or nerve plexus of interest Which is a good indicator that it is a good option in these patients when opioids are not an option. Doses of the continuous PNB are titrated to patient comfort while maintaining a level of consciousness needed for communication and cooperation. ** Peripheral nerve blocks can contain opioids!!! In most instances they probably do. It is imperative that the pts status on naltrexone is made known to the team and that opioids are not added to the block sPNB- single shot peripheral nerve block Refers to a one time injection of local anesthetic adjacent to the peripheral nerve or plexus Can last anywhere from 1-2 hrs up to >24hrs depending on the dose/conc/pharmacology etc… The major limitation of sPNB is the short duration of action of most local anesthetics. As such, sPNB is best suited for surgical procedures in which postoperative pain is not expected to exceed hours in duration; otherwise, patients are at risk for significant rebound pain after discharge Administration of larger volumes or higher concentrations of local anesthetics may increase the duration of block but also increase the risk of motor block and LAST cPNB- continuous infusion peripheral nerve block A good choice when pt will need prolonged anesthesia >24hrs Drugs administered through a percutaneously placed catheter placed adjacent to the peripheral nerve or plexus These costs include infusion pumps, catheters, and other supplies; local anesthetic medications; and provider time required for patient education and follow-up Continuous block devices – onQ pumps and…………. Girish Joshi. “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities.” Journal of Clinical Anesthesia, 10 Aug Pubmed, Accessed 23 Aug. 2017

Peripheral Nerve Blocks
Can contain many combinations of drugs Local anesthetics Corticosteroids Sodium bicarbonate Epinephrine Often contain an opioid for additional analgesia Avoid in patients on ERN

Additives Sodium Bicarbonate Epinephrine Corticosteroids
Used to decrease the time to onset of a block by ensuring molecules are in their uncharged, basic form to cross the nerve membrane Epinephrine Vasoconstrictor to slow absorption into tissues which can decrease toxicity and prolong duration of block Corticosteroids May help to prolong analgesia after PNB Neal JM, Gerancher JC, Hebl JR, et al. Upper extremity regional anesthesia: essentials of our current understanding, Reg Anesth Pain Med 2009; 34:134. Bedder MD, Kozody R, Craig DB. Comparison of bupivacaine and alkalinized bupivacaine in brachial plexus anesthesia. Anesth Analg 1988; 67:48. Bjørn S, Linde F, Nielsen KK, et al. Effect of Perineural Dexamethasone on the Duration of Single Injection Saphenous Nerve Block for Analgesia After Major Ankle Surgery: A Randomized, Controlled Study. Reg Anesth Pain Med 2017; 42:210. Neal JM, Gerancher JC, Hebl JR, et al. Upper extremity regional anesthesia: essentials of our current understanding, Reg Anesth Pain Med 2009; 34:134.

Peripheral Nerve Blocks
Risks to consider Perineural hematomas Neurologic complications Tingling, pain on pressure, pins and needles Local anesthetic systemic toxicity (LAST) Dose-dependent Metallic taste, tinnitus, perioral numbness, seizure, cardiac arrest, death Risks: regardless of technique or block location, there is a risk of vascular puncture and bleeding, nerve damage etc… Perineual hematoma – can be caused by inadvertent puncture of nearby vascular structures, especially in locations where application of pressure to the puncture site is not possible OR a where an expanding hematoma would not be apparent Patients with an abnormal coagulation status have an increased risk of these bleeding complications Neurologic complications are of particular concern because the duration of symptoms can extend for weeks or months after surgery [24,25]. These events are typically described by patients as tingling, pain on pressure, or pins and needles, and can be associated with both sPNB and cPNB LAST: Can occur whenever local anesthetics are administered, and can occur with all local anesthetics and any route of administration. Signs and symptoms are dose dependent and range from metallic taste, tinnitus, and perioral numbness to seizure, cardiac arrest, and death Girish Joshi. “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities.” Journal of Clinical Anesthesia, 10 Aug Pubmed, Accessed 23 Aug. 2017

Epidural with Local Anesthetics
Can be used for anesthesia of abdomen, pelvis, and lower extremities Performed by placing a catheter into the epidural space Using the same combinations of anesthetic and adjuvants as used in peripheral blocks Epidural anesthesia may be used for treatment of pain in the abdominal, pelvic, and lower extremities and, less commonly, thoracic injuries/procedures. The usual technique involves siting a catheter in the epidural space. LA solution and adjuvants (similar to PNB) are administered through the catheter, to initiate and maintain anesthesia for the duration of the surgical procedure.  opioids are often added to epidural anesthesia to enhance the analgesic effects but the pts medication history (use of ERN) needs to be made clear to the entire team. Catheter-based spinal/epidural anesthesia allows prolonged anesthesia and titration of the onset of the anesthetic. Single-shot spinal or epidural anesthesia is limited to the duration of action of the injected drug. Spinal anesthesia is usually administered as a single shot, whereas epidural anesthesia is usually administered via a catheter (thus it is a continuous technique), and Combined Spinal Epidural anesthesia combines the two, single shot into spine as well as continuous infusion through catheter. Veering BT, Cousins MJ. Epidural neural blockade. In: Cousins & Bridenbaugh's Neural Blockade in Clinical Anesthesia and Pain Medicine, 4th ed, Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh PO (Eds), Lippincott Williams & Wilkins, Philadelphia 2009.

Epidural with Local Anesthetics
Post Dural Puncture Headache (PDPH) Frontal or occipital headache Within 6 to 72 hours of the procedure Occurs due to inadvertent puncture of the dura Results in leakage of cerebral spinal fluid Headache can last days without treatment Treatment for PDPH Epidural blood patch: Placement of an epidural blood patch is a relatively simple procedure in which autologous blood is injected epidurally at or near the site of the prior LP. Epidural blood patching works via two mechanisms. The early, almost immediate, effect is related to volume replacement resulting from dural tamponade, and the latent effect results from sealing of the cerebrospinal fluid leak. Adverse effects are uncommon but include back pain, leg paresthesias, and fever. Some patients require more than one epidural blood patch before headache relief is achieved Alternate therapies: Other agents that have been evaluated for the treatment of PLPHA in small controlled trials or case series include oral and intravenous caffeine, epidural saline, intramuscular adrenocorticotropic hormone (ACTH) and intravenous synthetic ACTH, oral gabapentin, IV hydrocortisone, oral theophylline, and subcutaneous sumatriptan. Of these, the limited available data suggest modest effectiveness for gabapentin, hydrocortisone, and theophylline. Kuntz KM, Kokmen E, Stevens JC, et al. Post-lumbar puncture headaches: experience in 501 consecutive procedures. Neurology 1992; 42:1884.

Treatment of PDPH Epidural blood patch Alternate therapies
Blood is injected epidurally at or near the site of the prior LP Volume replacement and sealing of the CSF leak Alternate therapies The limited available data suggest modest effectiveness for gabapentin, hydrocortisone, and theophylline Adverse effects of an epidural blood patch are uncommon but include back pain, leg paresthesias, and fever. Some patients require more than one epidural blood patch before headache relief is achieved ACTH adrenocorticotropic hormone NEED A REFERENCE ON THIS SLIDE Boonmak P, Boonmak S. Epidural blood patching for preventing and treating post-dural puncture headache. Cochrane Database Syst Rev 2010; :CD 27.Sandesc D, Lupei MI, Sirbu C, et al. Conventional treatment or epidural blood patch for the treatment of different etiologies of post dural puncture headache. Acta Anaesthesiol Belg 2005; 56:265.

Technique Injection into epidural space vs. around peripheral nerve plexus Technique is important Inappropriate placement can be dangerous and very uncomfortable for the patient

Barriers to Epidural Use
Coagulation status Sepsis or infection at the site Increased intracranial pressure Low platelet count Uncorrected hypovolemia Anesthesiologists may be required to follow patient until epidural is removed

Test Your Knowledge Which of the following is not an FDA approved indication for the use of Extended-Release Naltrexone? Alcohol dependence Opioid dependence Opioid detoxification All of the above

Test Your Knowledge Which of the following doses of ketamine is appropriate for the management of severe pain in a patient who is on ERN and arrives at the ED with a broken femur s/p MVA? mg/kg bolus followed by mg/kg/min mg/kg bolus followed by 0.5 mg/kg/min mg/kg bolus followed by mg/kg/hr mg/kg bolus followed by 1 mg/kg/hr

Take Home Points Identify appropriate non-opioid analgesic treatment strategies for the management of severe, acute pain in patients on ERN Providing pain relief is challenging Use combinations of medications Educate patients and other providers Utilize an interprofessional approach We use opioids as a safety net because we know they are effective and they are an easy option when a patient is in acute pain Combinations are usually the best option, other classes, risky meds, procedures etc... Don’t forget about non-pharm things that can help – ICE, HEAT, WRAPS, SPLINTS, ETC Choosing an agent (or agents) depends on the severity of the pain and the nature of the injury Generally speaking you use clinical judgement Broken finger or bad muscle sprain vs. severe car crash or emergency surgery

Strategies for Acute Pain Management in Patients on Extended-Release Naltrexone
Megan T. Mitchell, PharmD PGY1 Pharmacy Resident UConn John Dempsey Hospital

Eastern States Residency Conference

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