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Levorphanol, the Forgotten Opioid: a novel approach to treatment of an acute, severe case of Treatment-Induced Neuropathy of Diabetes
Insulin Neuritis, otherwise known as Drug-Induced Neuritis or Treatment-Induced Neuropathy of Diabetes (TIND), is a painful, acute condition that develops in Type 1 or 2 Diabetics in which correction of chronic hyperglycemia is rapidly obtained. Though the condition was first described in 1933 by Caravati, in which a patient developed severe neuropathic symptoms which both began and resolved with the initiation and subsequent discontinuation of her insulin treatment, respectively, it is a condition that as a whole has gone largely unnoticed in the literature, and for which clear treatment regimens have seemed to elude development by the medical community. Despite this, it is believed to be more prevalent than previously thought, appearing in upwards of 10% of patients with neuropathy related to hyperglycemia.1 On average, reviews of the literature indicate that it appears to affect those in which the HbA1c levels are corrected rapidly, particularly those in which it is reduced by at least three points in three months or less.1
Our patient was a previously healthy 31 year-old male with a medical history significant only for a recently treated pilonidal cyst prior to the unusual onset of his Type 1 Diabetes Mellitus diagnosis over the winter in which he was found to be in severe Diabetic Ketoacidosis with an HbA1c level of 15.7%. This was rapidly corrected to an A1c of 8.7% in under 6 weeks. Around this time, the patient had started to develop bilateral lower extremity numbness and a painful, burning sensation in his lower extremities with radiation to the abdomen and intermittent cramping that had been worsening over the prior three months—an overall clinical picture consistent with a Treatment-Induced Diabetic Peripheral Neuropathy. He denied any history of tobacco, alcohol or other drug use. Laboratory values and physical exam were within normal limits with no focal neurological deficits noted. His skin was exquisitely sensitive to touch, implicative of severe allodynia, to the extent that he had been unable to wear pants or allow anything to touch the skin of his lower extremities. He reported paresthesias to a limited
(continued) degree in both legs. He denied weakness, specifically, but reported a progressive inability to perform daily tasks due to the intractable neuropathic pain. He had been unable to go to work, and had lost a significant amount of weight unintentionally. He had been prescribed hydrocodone-APAP, Duloxetine 60 mg daily, and Gabapentin 3000 mg daily by his PCP with little to no relief as an outpatient. He was then referred to neurology services who completed a Lidocaine infusion twice at a rate of 3 mg/kg/hr as an outpatient, initially with mild relief and then with limited to no relief. He had now essentially become near-crippled by the intense pain radiating from his lower extremities, that he described as extending occasionally as far up as his chest. He was thusly instructed to come to the hospital for inpatient pain stabilization.
Once admitted, the patient was weaned off of Gabapentin due to prior inefficacy and switched over to Pregabalin, which was slowly titrated upwards to a dose of 200 mg three times daily, given Tramadol for breakthrough pain, as well as being started on a Ketamine infusion, secondary Lidocaine infusion, and around-the-clock intravenous Ketorolac. He was given Oxycodone IR for breakthrough pain. He was continued on Duloxetine and titrated upwards. Of the above modalities, the patient felt that the first time he had obtained any relief from the severe 10/10 pain was with the Ketamine infusion—he had described this as a persistence in the conscious acknowledgement of ongoing pain signals, but that he “did not care” about the pain, and that in this sense it allowed him to move about more freely and feel relief. Unfortunately, following the discontinuation of the ketamine after maximum duration of medication permissible, the patient reported that pain levels began to return to baseline approximately 4 hours after cessation of the infusion. He was then started on Tapendatol 100 mg tablets as needed, on which he purported feeling overmedicated. This dosing was adjusted until ultimately he settled on 75 mg Tapendatol four times daily, in addition to Duloxetine 90 mg daily, Pregabalin 200 mg TID, and oxycodone as needed. On this regimen the patient felt his pain had leveled at a 7-8 out of 10 on the Numeric Pain Rating Scale. While this was admittedly unpleasant for him, it was sufficient enough to be discharged to outpatient treatment with the intention to tweak his regimen and possibly trial a spinal cord stimulator.
He obtained an MRI of the lumbosacral spine in preparation for this trial, which had not shown any abnormalities. Ultimately, despite experiencing parasthesias as a result of the stimulator trial, he felt that the underlying painful discomfort persisted to an intolerable degree. Since he had failed to sustain any clinically sufficient response to the typical and more commonly utilized regimens presented herein, he was placed on a trial of Levorphanol due to its multi-modal receptor effect and limited cross-tolerance with other opioids, among other potential benefits. He was placed on a dose of two 2 mg tablets three times daily, with one additional tablet for breakthrough purposes, while concurrently decreasing his other as-needed medications. The patient had notable reservations about this initially, as he purported to receive the most benefit to his pain levels from the oxycodone, though admitted that even this had to be combined with Tapendatol for even tolerable and minimal benefits. Incredibly, he had a significant response to the addition of Levorphanol to his regimen. Within 3 weeks he had eliminated use of oxycodone, reduced his levorphanol dose, and purported his pain level to be 50% decreased from prior maximum levels. In addition, he had returned to near baseline daily activities, working, and had gained nearly 30 pounds that he had lost while at the peak of his illness.
Neuropathic pain has classically been among the more difficult types of pain to treat. Assessment of the underlying physiological basis for this pain has rested primarily with the concept that there is over activation of the NMDA receptor by glutamate, and this is perhaps why classic analgesics, such as primary Mu-opioid agonists, have typically provided minimal relief, all-the-while bringing with them the inconvenient side effects associated with typical Mu-agonists like dependency, hyperalgesia, constipation, tolerance, etc. Even other mixed-receptor medications such as methadone, often more effective in neuropathic pain treatments, come with their own set of risks such as QT-prolongation, and propensity to have drug-drug interactions due to their method of elimination via the cytochrome system in the liver. Levorphanol has a wide range of ascending and descending pain pathway mediator-effect, including mu, delta, kappa, NMDA, and SSRI/SNRI affinities.3 Further still, it shows far less cross-tolerance to other opioids than one would expect, allowing for low initial dosing and slowly titrating upwards as needed. It has no known cardiac risks. Levorphanol has been found to be well-absorbed orally, unreliant on p-glycoprotein in the gut for absorption, and is thus well-suited for outpatient treatment.5 It has minimal propensity for drug-drug, drug-food interactions, and does not have the same risk for genetic variation in metabolism like other opioids due to its avoidance of cytochrome metabolism. It has a longer half life (11-16 hours) and duration of analgesia (6-12 hours) than others in its class.4 While the exact pathophysiology of TIND is being investigated, the clearly severe, neuropathic nature of this disease-state lends itself to a need for novel approach, especially given the severe nature of this pain, and how refractory it has been to typical pain management.
In a case of refractory, severe neuropathic pain such as herein, the choice of treatment has been inconclusive in the literature. Evidence is scarce in supporting opioid treatment for such pain, however, Levorphanol, somewhat of a “forgotten” opioid, is a potent analgesic whose multi-modal receptor affinity makes it unique in its class, particularly with respect to its NMDA antagonism and SNRI/SSRI activity. NMDA receptor activation by glutamate is a correlative etiology of neuropathic pain in general, and this may suggest why our patient not only received initial relief the most from Ketamine, but why levorphanol succeeded in stabilizing him as an outpatient in a setting where Ketamine has not yet become readily available, convenient, or realistic as an outpatient treatment modality. While its wide range of receptor activity puts patients on levorphanol at risk of some adverse effects such as psychotomimetic symptoms including hallucinations, its positive attributes may far outweigh these risks, particularly in treating severely refractory chronic pain conditions such as TIND.