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14 Articles in Volume 19, Issue #5
Agonism and Antagonism of the Muscles of the Shoulder Joint: An SEMG Approach
Analgesics of the Future: The Potential of IV Formulations for Post-Op Treatment of Pain
Blood Biomarkers Show Promise for Precision Pain Management
Can I Call Myself a “Pain Specialist?”
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 2)
Fear-Avoidance and Chronic Pain: Helping Patients Stuck in the Mouse Trap
How to Avoid Patient Alienation When Discussing Stress
Managing Phantom Limb Pain with Medication
Nerve Blocks Lead to Improved Quality of Life
Sacroiliac Joint Dysfunction: New Methods in Evaluation and Management
SCS Therapy in a Patient with Advanced Bilateral Kienbocks
Thoracic Epidural Abscess with Cord Compression Following a High-Frequency SCS Trial
What is the evidence to support clonidine as an adjuvant analgesic?
What’s In A Name? In This Case, That Which We Call Addiction Is Not Dependence

Analgesics of the Future: The Potential of IV Formulations for Post-Op Treatment of Pain

A review of the emerging intravenous formulations of known analgesics: tramadol and meloxicam.
Pages 47-49

Tramadol is a centrally acting mu opioid receptor agonist as well as an inhibitor of serotonin and norepinephrine reuptake that FDA approved as a tablet for the treatment of moderate to severe pain management in 1995. More recently, a new intravenous (IV) formulation was developed for the treatment of moderate to moderately severe post-operative pain. IV tramadol is already approved for use in Europe and has had promising results from its Phase 3 trials in the United States for post-operative pain management.1-3

Meloxicam is a preferential cyclooxygenase-2 (COX-2) inhibitor NSAID that contains antipyretic, analgesic, and anti-inflammatory properties; FDA approved the drug in 2000 as a tablet for the management of osteoarthritis and rheumatoid arthritis. An IV formulation of this medication is under regulatory review for the treatment of moderate to severe acute pain. The IV formulation is made with a novel NanoCrystal technology (Alkermes) to enhance its bioavailability. Pharmacokinetic information on the NanoCrystal has not been published, but a standard population pharmacokinetic model presented at a conference demonstrated that body weight and renal function had an effect on clearance. The theoretical benefit of IV meloxicam over its tablet formulation is a quicker onset of action.4-6

The Data

Tramadol

A Phase 3 multicenter, double-blind, placebo-controlled trial (n = 409) compared IV tramadol 50 mg, IV tramadol 25 mg, or placebo for post-operative pain following a bunionectomy surgery.2 The medications were administered at 0, 2, 4, and once every 4 hours thereafter. The primary endpoint was improvement in Sum of Pain Intensity Difference over 48 hours (SPID48). Secondary endpoints included SPID24, total consumption of rescue medication, and Patient Global Assessment. Researchers found a statistically significant improvement in SPID48 with the 50-mg dose compared to placebo. The IV tramadol was found to be generally well-tolerated with adverse events of nausea, vomiting, and somnolence being most common and classified as mild or moderate.

A second Phase 3 trial in patients following abdominoplasty surgery was completed with results announced in June 2019. This multicenter, randomized, double-blind, placebo-controlled trial included 370 patients. Subjects were randomized in a 3:3:2 ratio to a post-abdominoplasty regimen of 50 mg IV tramadol, placebo, or 4 mg IV morphine at 0, 2, 4, and every 4 hours after up to 13 doses over 48 hours. This trial achieved the primary endpoint, which was a statistically significant improvement in SPID24 compared to placebo for post-operative pain. This trial also successfully reached all secondary endpoints. The IV tramadol was compared to IV morphine 4 mg and demonstrated similar safety and efficacy to the comparator.3

Meloxicam

Phase 2 trials evaluating IV meloxicam after surgical procedures found that it exhibited onset of analgesia within 15 minutes or less with maintenance of the analgesic effect through the 24-hour dosing period. IV meloxicam underwent two randomized, multicenter, double-blind, placebo-controlled trials evaluating a dose of 30 mg following major elective surgeries.7-9 The first Phase 3 trial found a statistically significant decrease in SPID48 compared to placebo as well as opioid-sparing effects.6 In the second Phase 3 trial, IV meloxicam was associated with a 23.6% (P = 0.0531) reduction in total opioid use compared to placebo. The most common adverse effects were nausea, constipation, and vomiting and were classified as mild or moderate.5

Discussion

Both of these novel medications take a new approach to two medications that are familiar to the pain management community. They may soon act as additional tools within the pain practitioner’s toolbox. IV formulations allow for faster onset which may be particularly helpful in an in-patient or emergency department setting. The Phase 3 trial results on IV tramadol are promising for pain management and may be helpful in reducing usage of Schedule II opioids, which carry a higher risk of abuse and dependence compared to oral (PO) tramadol. However, it is important to keep in mind that pain is subjective and decreases in SPID48 scores do not always correlate to a comfortable pain level for patients in clinical practice. Essentially, tramadol has been described as a post-operative option that “bridges the gap” between NSAIDs and conventional Schedule II opioids for moderate to moderately severe pain. That being said, healthcare providers must remember that tramadol is a weak opioid and its effects vary widely in patients based on CYP2D6 genotypes. Therefore, tramadol may not always be an effective option for managing moderately severe post-operative pain.

IV meloxicam has shown to be efficacious for pain reduction and its opioid-sparing effects. The medication has not been able to gain FDA approval to date due to delayed onset of action as well as concerns in using it for monotherapy in an acute pain setting. Due to its long half-life, however, IV meloxicam is unique in that it was only administered every 24 hours in clinical trials. However, in an acute pain setting, pain levels may change and breakthrough pain medications may be needed, making a long-acting IV NSAID less desirable. IV meloxicam, if approved, would be the fourth IV NSAID on the market, joining ibuprofen, indomethacin, and ketorolac. No studies have been done comparing the efficacy of IV meloxicam to these available products, to date. Patients with significant cardiovascular disease, renal or hepatic impairment, and a recent bleeding event were excluded from clinical trials which renders a large portion of the general population ineligible for this medication. The key for IV meloxicam may be finding the right niche for a quicker onset and longer-acting IV meloxicam.

Our PPM Editors-at-Large gave IV formulations for post-op pain a 3.5 out of 5. Read the full review below. (Source: 123RF)

PPM Editors-at-Large Weigh in on Post-Op IV Formulations for Pain

Hospitals are focused on opioid-sparing techniques as part of enhanced recovery after surgery [ERAS] protocols and, considering concerns about opioid misuse and/or prolonged use, new IV formulations in the acute care setting are certainly welcome. The authors of the main report herein aptly point out that tramadol has weaker mu opiate activity compared to full agonists, which may have positive and negative benefits. Less respiratory depression and abuse potential have been purported with tramadol, although it may not be appropriate when a patient’s severe pain requires pure mu agonist titration. Notwithstanding, tramadol does offer an important alternative alone or in combination with adjuvant analgesics, and it certainly may serve as an alternative to or a step-down from initial full agonist opioids post-operatively. Outside of the US, it is a commonly utilized first-line agent for acute postoperative pain.

Clinicians should recognize the same precautions for IV tramadol as its PO (oral formulations), including its multiple mechanisms of action, drug:drug interactions, unique enantiomeric biochemistry, and metabolism. Caution should be taken when considering continuation of IV tramadol as PO in elderly patients on polypharmacy and those on concomitant antidepressants.

Looking at IV meloxicam, it does appear to offer a much needed and novel IV alternative compared to currently available ketorolac and ibuprofen when considering the benefits of COX-2 selectivity. For years, IV parecoxib has been offered outside the US as a COX-2 selective alternative to traditional IV NSAIDs, which may have clinical benefits when bleeding risk is elevated. In addition, with a trend toward reducing opioid use prior to and following discharge, this drug comes at an opportune time. In cases of molar extraction among young patients, for example, using a COX-2 selective IV formulation may have an impact on reducing the pain and inflammation seen post-operatively and hence spare the need for opioids.

Although neither is a new chemical entity, both IV tramadol and meloxicam should make useful additions to the practitioner’s acute pain toolbox. Overall, we give these novel IV formulations 3.5 out of 5 stars.

*Review by Jeff Gudin, MD & Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB. Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewers’ expertise and opinion. For this particular review, Dr. Gudin discloses that he has been involved as a consultant to the developers of both IV tramadol and IV meloxicam.

Last updated on: December 4, 2019
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