We present a case series in which a combination of 1 gm magnesium(500 mg/ml, American Reagent), 100 mg lidocaine (20 mg/ml,Hospira), and 15 mg ketorolac (30 mg/ml, Hospira) successfully managedopioid resistant pain in the Post-Anesthesia Care Unit (PACU).The medicines were combined in the same syringe and diluted to 10 mlwith saline. To avoid injecting magnesium and lidocaine too rapidly,the medicines were administered as a two ml bolus immediately andthen one ml every 30 seconds by the clock (4.5 minutes total). Postoperativeanalgesia typically involves as needed IV opioids; unresponsivepatients can present a demanding therapeutic challenge. Anecdotally,the magnesium, lidocaine, and ketorolac (MLK) combination hasproven efficacious with minimal side effects at our home institution.

Five consecutive patients with opioid resistant, post-operative painthat were administered MLK in the PACU are presented. Opioid resistantpain, defined as greater than 7/10 pain despite 8 mg of morphineor equivalent, is consistent with prior studies [1]. At our home institution,typical post-operative analgesic orderes are 0.2 mg hydromorphoneevery 10 minutes as need for pain with a maximum of 2 mgto be administered. Pain scores were recorded 30 minutes after MLKadministration. Patient heart rate, respiratory rate, blood pressure, andsedation were continuously monitored.

A 23 year-old male presented for wound vacuum change and fasciotomyclosure eight days following Superficial Femoral Artery graft,Common Femoral Vein ligation, and left leg fasciotomies secondaryto multiple gunshot wounds. In the 24 hours preceding surgery,he required 36 mg morphine IV and six vicodin tablets. Surgery wasperformed under spinal anesthesia (10 mg tetracaine, 12.5 mcg fentanyl,and 100 mcg epinephrine). After spinal resolution, despite 100mcg fentanyl, 2 mg hydromophone and 25 mg meperidine, he reported8/10 pain in the PACU. Thirty minutes following MLK administration,pain improved to 3/10.

A 43 year-old male with no past medical history (PMH) underwentopen ventral hernia repair under general anesthesia (GA). He received350 mcg of fentanyl during the surgery. Pain was uncontrolled in thePACU despite 3.2 mg hydromorphone. MLK administration improvedpain from 7/10 to 3/10 and facilitated the patient’s discharge home.

A 20 year-old male underwent GA for Open Reduction InternalFixation (ORIF) of a left distal radius fracture. During the procedure,the patient received 350 mcg of fentanyl and 2 mg of hydromorphone. In the PACU, despite 8 mg of morphine, the patient reported 9/10 pain.Following MLK administration, pain improved to 6/10. He was subsequentlydischarged home.

A 63 year-old female with PMH of colon cancer, proctocolectomy,and diverting ileostomy presented for colostomy take down. Medicationhistory included prior FOLFOX chemotherapy, bupropion for depression,and vicodin and gabapentin for chronic pain. She received150 mcg of fentanyl during GA. Despite 2 mg of hydromorphone in thePACU, she reported 10/10 pain. MLK administration decreased painto 5/10.

A 26 year-old male underwent GA for right tibia/fibula ORIF forinjuries sustained during a motor vehicle accident. PMH was significantfor newly diagnosed HIV and panic attacks. Intra-operatively, thepatient received 350 mcg of fentanyl and 1.4 mg of hydromorphone.In the PACU, 3.2 mg hydromorphone did not control pain. Initially, 30 minutes following MLK administration, pain improved from 10/10to 4/10. However, the effect was transient. Pain regressed to 8/10 in anadditional 30 minutes. He was discharged from the PACU to the floorwithout receiving additional opioids.

Aggregate patient data is presented in Table 1. Mean intra-operativeand PACU morphine doses were 30 mg and 16.8 mg. FollowingMLK administration, the mean pain score decreased from 8.8 to 4.2.The mean pain score reduction was 52.6 percent; the median was 57.1percent.

Magnesium, lidocaine, and ketorolac are approved medicationsthat are used safely in daily, clinical practice. Since magnesium, lidocaine,and ketorolac all work by different mechanisms, they should logically exhibit synergistic instead of additive effects; analagous to theinteraction between opioid and non-steroidal anti-inflammatory drugs [2]. While ketorolac is a common opioid-sparing analgesic, magnesiumand lidocaine are more investigational.

Magnesium antagonizes prejunctional calcium, inhibits acetylcholinerelease at the neuromuscular junction, stabilizes the membrane,decreases catecholamine release, and antagonizes the NMDA receptor [3]. Nerve injury creates a burst of glutamate-mediated activity at NMethyl-D-Aspartate (NMDA) receptors that is excitotoxic to inhibitoryinterneurons in the dorsal horn of the spinal cord, leads to paindisinhibition, and contributes to persistent pain [4]. Magnesium exertsits effects on the NMDA receptor by physically occluding the receptorpore and allosterically modulating the NR2B subunit, a subtype thatcontributes preferentially to pathological processes linked to glutamateover-excitation [5]. Previously, a randomized prospective trial demonstratedthat a 8 mg/kg IV magnesium infusion during surgery significantlylowered post-operative pain scores for the first 12 hours anddecreased post-operative morphine requirements for the first 24 hourscompared with placebo following lower extremity orthopedic surgery [6].

Lidocaine is an amide local anesthetic that blocks voltage-gated sodiumchannels to prevent membrane depolarization and action potentialpropagation. As afferent noxious stimuli transmission depends onthis process, if the sodium channels are blocked, then noxious stimulicannot be transmitted to the central nervous system. Lidocaine bindsto the intracellular portion of voltage-gated sodium channels to prevention movement through the channel. In addition to this classicmechanism of action, lidocaine augments the inhibitory, cholinergic,descending pain pathway; releases endogenous opioids; and reducespost-synaptic NMDA depolarization in the spinal cord [7]. A recentmeta-analysis examined the effects of a peri-operative lidocaine infusionand concluded that lidocaine decreased post-operative pain andopioid requirements. Additional benefits included decreased ileus,decreased postoperative nausea and vomiting (PONV), and decreasedhospital length of stay [8].

Repeated, ongoing injury and exposure to inflammatory mediatorssensitizes functional peripheral nociceptors and activates dormantones. Through neural plasticity, inflammatory nociceptor sensitizationdecreases threshold and increases responsiveness so that subsequentafferent, nociceptive inputs are amplified [9]. Ketorolac is used to decreaseinflammation and potentially prevent peripheral sensitization.A recent meta-analysis demonstrated that a single systemic ketorolacdose reduced postoperative pain, opioid consumption, and PONV [10].

This case series demonstrated that MLK can safely and efficaciouslymanage opioid resistant post-operative pain. While opioids were often initially effective in the patients presented, peripheral and central sensitizationmost likely lead to opioid resistance. The MLK bolus was effectivein patients with PMH of anxiety, depression, and chronic pain.While one patient experienced only transient benefits from the onetimeMLK bolus, continuous magnesium or lidocaine infusion possiblycould have produced longer-lasting analgesia. Additionally, the PACUphysician administered the boluses over 4.5 minutes. This extra time atthe bedside allowed for discussion of the MLK bolus and provision ofemotional comfort.

Perhaps this additional physician-patient interaction accounts forsome of the benefits observed in this case series.

Appropriate pain management is critical; it maintains patient functionalstatus, improves emotional well being, enhances quality of life,decreases hospital stay, and prevents readmission (ASA). Additionally,the preponderance of evidence demonstrates that acute post-surgicalpain predicts chronic pain. More efficacious acute pain treatment is humane,prevents chronic pain, decreases complications, and facilitatesrecovery. The department’s anecdotal results with the magnesium, lidocaine,and ketorolac combination have proven so compelling that arandomized, prospective, placebo-controlled trial is being prepared totest this novel, non-opioid combination on uncontrolled post-operativepain.

This case series (HS-11-00707) was approved by the USC IRB on 23 December2011. The IRB Administrator was Marie Reyes. She may be reached via emailat marierey@usc.edu.