Tapentadol, Buprenorphine, and Levorphanol for the Treatment of Neuropathic Pain: a Systematic Review.

PURPOSE OF REVIEW: The objective of this systematic review is to present the available evidence for the utilization of the atypical opioids tapentadol, buprenorphine, and levorphanol for the treatment of neuropathic pain. RECENT FINDINGS: In total, 1619 articles were retrieved of which 10 studies were included. Of 5 included studies pertaining to tapentadol, 4 studies show tapentadol monotherapy to be effective for the treatment of diabetic peripheral neuropathy or chronic, radiating low back pain. Of the 3 studies included for buprenorphine, only one was a randomized controlled trial found not to have a statistically significant reduction in pain with TD buprenorphine likely due to very high withdrawal rates during the trial. Only 2 case reports were included from the available literature for levorphanol providing low-quality anecdotal evidence. The role of tapentadol, buprenorphine, and levorphanol for neuropathic pain conditions requires robust research including randomized controlled trials to evaluate their efficacy and safety.

Evolution of Analgesic Tolerance and Opioid-Induced Hyperalgesia Over 6 Months: Double-Blind Randomized Trial Incorporating Experimental Pain Models.

Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic nonmalignant pain patients entered a 6-month long, randomized, double-blind, dose-response, 2-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35 and 122 morphine equivalents. Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, brief pain inventory scores, and results of the brief thermal sensitization model at 5 opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14 to 300; average addition 105 morphine equivalents. After observed dosing, the brief thermal sensitization area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0 to 100 visual analog scale pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but 8 completed with higher visual analog scale ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. TRIAL REGISTRATION: NCT00275249 Evolution of Analgesic Tolerance With Opioids PERSPECTIVE: A double-blind, 6-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and OIH. Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic randomized controlled trial design.

Can levorphanol be used like methadone for intractable refractory pain?

BACKGROUND: Levorphanol has been reported to provide analgesia at doses that suggest it does not act like other pure agonist opioids. A dual effect of action on both opioid receptors and n-methyl, d-aspartate (NMDA) receptors has been proposed to be responsible for this effect. METHOD: Case series of patients treated with levorphanol when pain did not respond adequately to other opioids, including methadone. RESULTS: During a 5-year period in a single palliative medicine practice, 20 of 244 patients with chronic nonmalignant pain in a palliative care clinic and 11 of 1508 terminally ill patients enrolled in hospice care whose severe chronic pain was not relieved by treatment with other opioids were treated with oral levorphanol. Of those 31 patients, 16 (52%) reported excellent relief of pain and 7 (22%) reported fair relief for a total response rate of 74%. DISCUSSION: These results suggest that levorphanol has a role in the treatment of pain syndromes that are refractory to other opioids. The pattern of relief seen in this case series is similar to that reported for methadone. Could it be that levorphanol may have a role like methadone for pain that is poorly controlled with other pure agonist opioids? We summarize what is known about levorphanol and provide a table for converting other opioids to levorphanol that was used for this case series.

Levorphanol: the forgotten opioid.

BACKGROUND: Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a strong opioid that is the only available opioid agonist of the morphinan series. Levorphanol was originally synthesized as a pharmacological alternative to morphine more than 40 years ago. It is considered a step-3 opioid by the World Health Organization (WHO) and has a greater potency than morphine. Analgesia produced by levorphanol is mediated via its interactions with mu, delta, and kappa opioid receptors. Levorphanol is also an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence that levorphanol may inhibit uptake of norepinephrine and serotonin. Similar to morphine, levorphanol undergoes glucuronidation in the liver, and the glucuronidated products are excreted in the kidney. Levorphanol can be given orally, intravenously, and subcutaneously. OBJECTIVE: This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this often overlooked step-3 opioid. CONCLUSION: The long half-life of the drug increases the potential for drug accumulation. Levorphanol has clinical efficacy in neuropathic pain.

Oral opioid therapy for chronic peripheral and central neuropathic pain.

BACKGROUND: Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied. METHODS: Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels. RESULTS: Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit. CONCLUSIONS: The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.

Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain.

The successful use of methadone in cancer pain has been supported by numerous case reports and clinical studies. Methadone is usually used as a second or third line opioid medication. As the use of methadone increases we are facing the challenge of converting methadone to other opioids as part of sequential opioid trials. Data on the equianalgesic ratios for the substitution of other opioids for methadone are lacking. We present prospective data on 13 consecutive rotations from methadone to a different opioid. The opioid rotation was followed by escalation of pain and/or severe dysphoria, not controlled by a rapid increase in the dose of the second opioid, in 12 of the 13 patients. Only one patient was successfully maintained on the second opioid after the discontinuation of methadone, while 12 patients required a switch back to methadone. We conclude that opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria. These symptoms may not improve despite upward titration of the second opioid. A uniformly accepted conversion ratio for substituting methadone with another opioid is currently not available. More data on the rotation from methadone to other opioids are needed.

An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity.

UNLABELLED: We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. IMPLICATIONS: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Dextromethorphan and levorphanol on dorsal horn nociceptive neurones in the rat.

Intrathecal administration of dextromethorphan and levorphanol and intravenous injection of dextromethorphan were tested on the electrophysiological response of deep multireceptive dorsal horn neurones to peripheral stimuli. Both blockade of C-fibre input to the cells and wind-up, the increase in C-fibre firing with repeated stimulus, were recorded. Intrathecal injection of levorphanol (0.25-100 micrograms) had a typical opioid effect, blocking the C-fibre input. Its affect on wind-up was dose-dependent, paralleled precisely the blocking effect on the C-fibre input and both effects were reversed by naloxone. Unlike levorphanol and other opiates, intrathecal administration of dextromethorphan (50-500 micrograms) blocked the C-fibre input and A beta response in parallel and was not reversed by naloxone. Wind-up was reduced by a maximum of 56% at the largest dose tested. Intravenous injection of dextromethorphan (5 mg/kg) also produced a reduction in wind-up but not in the C-fibre response.

I.v. infusion of opioids for cancer pain: clinical review and guidelines for use.

To assess the safety, efficacy, and use of continuous iv infusion (CI) of opioids for cancer pain, we reviewed the clinical experience of 36 patients who received 46 CIs. CI was always preceded by a period of repetitive dosing of opioids. Morphine was used in 36 CIs, methadone in four, hydromorphone in four, oxymorphone in one, and levorphanol in one. Mean doses during CI were the morphine equivalent of 17 mg/hour (range, 0.7-100) at the start, 69 mg/hour (range, 4-480) at the maximum, and 52 mg/hour (range, 1-480) at termination. Pain relief was acceptable during 28 CIs, unacceptable during 17, and unknown during one. There were few toxic effects other than sedation. Twenty-five patients died, 12 resumed im or oral opioids, six continued CI with a different opioid (yielding analgesia in two), and outcome was undetermined in three. This review suggests that (a) CI is safe, (b) analgesia may require rapid escalation of infusion rates, (c) patient response varies and lack of acceptable analgesia may occur in up to one-third, (d) ineffective CI with one drug may be followed by success with another, (e) CI should be preceded by a period of repetitive iv boluses with the same drug, and (f) guidelines can be developed which incorporate pharmacokinetic principles.

Excitatory effects of iontophoretically applied substance P on neurons in the nucleus tractus solitarius of the cat: lack of interaction with opiates and opioids.

The effects of iontophoretically applied substance P (SP), (D-Pro2, D-Trp7,9)-SP and (D-Pro4, D-Trp7,9,10)-SP were studied on neurons identified by their histological location in the nucleus tractus solitarius (NTS), their response to vagal or carotid sinus nerve stimulation and eventually their functional correlation with the central respiratory drive. Potent and consistent excitatory effects of SP were found supporting its role as a putative excitatory transmitter in the NTS. The effects of SP and L-glutamate (Glu) were differentiated by the relative insensitivity of SP-induced excitations to levorphanol and Met-enkephalin.

Simultaneous measurement of cholecystokinin- and vasoactive intestinal polypeptide-like immunoreactivity from cat frontal cortex in vitro: effect of morphine and D-Ala2-D-Leu5-enkephalin.

The two peptides vasoactive intestinal polypeptide (VIP) and cholecystokinin (CCK) have been demonstrated to be discretely distributed in the cerebral cortex. This distribution closely parallels the distribution of mu- and delta-opiate receptors in the frontal cortex. The basal efflux and potassium-stimulated release of VIP- and CCK-immunoreactivity was studied in the presence and absence of morphine and D-Ala2-D-Leu5-enkephalin (DADL), agents with relative affinity for the mu and delta receptors, respectively. The basal efflux of VIP- and CCK-immunoreactivity was not affected by these opiates; however, the potassium-stimulated release of VIP-immunoreactivity was profoundly inhibited in a dose-dependent manner by both morphine (ED50 = 1 X 10(-9) M) and DADL (ED50 = 3.02 X 10(-9) M). The inhibition produced by either morphine or DADL was shown to be reversed by naloxone.

Intracerebral opiates block the epileptic effect of intracerebroventricular (ICV) leucine-enkephalin.

Intracerebroventricular (ICV) injection of both enkephalin (100 micrograms) and morphine (200 micrograms produces characteristic electrographic seizures. Injection of low doses of either morphine or levorphanol into the lateral ventricle of the brain prior to the administration of epileptogenic doses of enkephalin can block the induction of such seizures. A similar trend was observed when either opiate preceded ICV morphine. Microinjections of both morphine (30 micrograms) or levorphanol (40 micrograms) into the periaqueductal gray area (PAG) or into the nucleus accumbens resulted in potent analgesia. However, only morphine injected into the nucleus accumbens was effective in blocking electrographic seizures induced by ICV enkephalin. On the basis of this and other previous findings we propose that the excitatory-epileptic and the inhibitory-antiepileptic action of opiates and opioids are mediated by two different systems. Furthermore, we propose that such systems may differ both in their anatomical distribution and in the classes of opiate receptors underlying their action.

Benefit from and tolerance to continuous intrathecal infusion of morphine for intractable cancer pain.

A patient with painful bilateral metastatic lumbosacral plexopathy from cervical cancer was treated with levorphanol tartrate (Levo-Dromoran), 4 mg orally every 4 hours, with poor pain relief. A lumbar subarachnoid catheter was then placed percutaneously. A bolus of 1 mg of morphine gave complete pain relief for 17 hours. Over the next week, the dose requirement increased to 10 mg/day, infused by an external pump. A permanently implantable infusion pump with a 50-cc drug chamber and flow rate of 3.4 cc/day was placed in the abdomen and attached to the lumbar subarachnoid catheter. The pump was refilled by percutaneous injection. Morphine was infused continuously at 15 mg/day, affording the patient increased mobility and no pain for 7 days. When the pain returned, the morphine dose was increased to 17.5 mg/day, and the patient was allowed to take oral Levo-Dromoran for pain. The intrathecal morphine dose was constant within 2-week periods, but was increased from 17.5 to 96 mg/day because of inadequate pain relief. Oral Levo-Dromoran intake averaged 3.4 mg/day. Levo-Dromoran intake was less during the 1st week of each 2-week cycle than the last week (mean 15.0 versus 38.0 mg/wk, p less than 0.05). No sedation or respiratory depression was seen.

Levorphanol:radioimmunoassay and plasma concentration profiles in dog and man.

A specific radioimmunoassay (RIA) procedure has been developed for the determination of the narcotic analgesic, levorphanol, in plasma using a rabbit antiserum to an albumin conjugate of (-)-3-hydroxy-N-carboxymethylmorphinan. Assay specificity was achieved by chromatogrphic isolation of levorphanol from plasma extracts on Sephadex LH-20 prior to analysis. The method has a limit of sensitivity of about 0.5 ng/ml of levorphanol using a 0.1 ml sample of plasma. Steady-state plasma concentrations of levorphanol have been determined for the first time in two cancer patients receiving chronic therapeutic doses of the drug. The plasma concentration-time profile for levorphanol following i.v. administration of 2 mg/kg to a dog declined biexponentially and the terminal elimination phase had a half-life of 2.4 hr. When another dog received orally 7 mg/kg of the drug in aqueous solution, the normalized area under the plasma concentration-time curve of intact levorphanol was less than 2% of the are observed after i.v. administration and suggests extensive "first-pass" metabolism of the drug in the dog.

Cellular and metabolic tolerance to an opioid narcotic in mouse brain.

1. Running activity and brain levorphanol concentration were measured in nontolerant and tolerant mice given various doses of (3)H-levorphanol.2. The principal factor responsible for tolerance in the mouse is a loss of sensitivity to the narcotic drug at the cellular level in brain; despite adequate brain concentrations, the pharmacological effects are diminished or absent.3. There is also metabolic tolerance; a given dose establishes a lower brain concentration in tolerant than in non-tolerant animals.4. The two kinds of tolerance are distinguished here and the contribution of each is assessed.