Opioids: The war on drugs

Approaches and methods to treat pain differ wildly, with opioid alternatives attempting to provide new and less aggressive means of pain management. As the global pharmaceutical industry strives to find a solution to the ongoing problems surrounding over-use of opioids, drug makers are challenging to get approval for several new compounds.

While there are limited number of alternative therapies currently approved, there is a growing number in late-stage trials some of which are being described as potential rising stars. 

Did you know?

Local anaesthetics can be used as an alternative to opioids: Trial results suggest that it can reduce opioid use by 78% in the first 48 hours after surgery. Find out more…

Read on to discover the priority targets being fast-tracked by the FDA, the results of current phase III trials, and those drugs in development tipped to be the next blockbuster. 

NGF inhibitors – harnessing potential

The FDA recently fast-tracked for approval a humanized monoclonal antibody which selectively targets, binds to and inhibits nerve growth factor (NGF). Though this class of therapy looks promising, US regulators had previously halted work on tanezumab and other NGF inhibitors over concerns about side effects.  Phase III trials on PF 4383119 (tanezumab) from Pfizer and Eli Lilly have now restarted and tanezumab is in phase III trials for pain associated with osteoarthritis, for chronic low back pain (positive results from TANGO study) and for cancer pain.

Relieving chronic pain from osteoarthritis of the knee or hip

Also, in phase III trials is the NGF inhibitor REGN 475 (fasinumab) from Regeneron and Teva billed as the main competitor for tanezumab. In 2018, the companies announced positive topline results from a Phase III study of REGN 475 in patients with chronic pain from osteoarthritis of the knee or hip. At week 16 analysis, the study met both co-primary endpoints and all key secondary endpoints. Fasinumab-treated patients experienced significantly less pain and significantly improved functional ability from baseline compared to placebo.

A new blockbuster?

Analysts have suggested that a successful NGF inhibitor could be a blockbuster, but warn that with this class of drug, safety will remain a question until long-term trial data becomes available. The companies agreed with the FDA to advance only the lower dose regimen.

Osteoclast inhibitors

Phase III trials are also underway for AXS 02 (disodium zoledronate tetrahydrate) from Axsome Therapeutics. This is an osteoclast inhibitor being developed as an oral, targeted, non-opioid, potentially first-in-class therapeutic for chronic pain. Studies are underway with AXS 02 in pain associated with knee osteoarthritis and the therapy is FDA fast-tracked. An Independent Monitoring Committee recommended that the CREATE-1 trial for complex regional pain be stopped while the COAST-1 trial for knee-osteoarthritis should continue. Also under development by Axsome is AXS 06, a Phase III-ready, oral, non-opioid which is a rapidly absorbed, once-daily medicine, consisting of a long-acting NSAID meloxicam combined with esomeprazole, a proton pump inhibitor, to reduce the risk of NSAID-associated gastrointestinal ulcers. AXS 06 is also being developed for the treatment of chronic osteoarthritis pain.

Targeting the capsaicin receptor

Centrexion Therapeutics have developed a synthetic capsaicin, CNTX 4975, which is FDA fast-tracked, and currently entering phase III trials for knee pain. It works by selectively targeting the capsaicin receptor (also known as TRPV1) that inactivates the nerve fibres transmitting pain signals to the brain.  In phase II trials, CNTX 4975 met its primary endpoint of a reduction in pain with walking through 12 weeks with high statistical significance and demonstrated a duration of effect of at least 24 weeks after a single dose.

Use of local anaesthetics as an alternative to opioids

Another strategy currently being explored is the use of local anaesthetics as pain relief, thereby reducing the need for analgesics such as opioids. Exparel (bupivacaine extended-release liposome injection) from Pacira Pharma is currently in trials for pain relief after surgery and relief of complex regional pain. It uses an extended release formulation of a local, non-opioid anaesthetic to cut pain. Trial results suggest that it can reduce opioid use by 78% in the first 48 hours after surgery. 

Heron therapeutics is following a similar path, with bupivacaine combined with anti-inflammatory meloxicam. Results show that with this combination, opioid use was reduced by a third in the first 72 hours after bunion surgery. The combination is also in phase III for Hernia repair.

Targeting different pathways for pain reduction

While conventional opioids target the mu opioid receptor to achieve pain reduction, researchers are looking to selectively target alternative opioid receptors, in particular the kappa and delta receptors which provide different pathways for pain reduction. Such drugs should have less effect on the central nervous system and so cause fewer of the problematic side effects associated with mu receptor agonists, including lower rates of addiction¹. Cara Therapeutics is currently testing its potential kappa-targeting painkiller Korsuva (difelikefalin) as both oral and IV formulation in phase III trials for post-surgical pain, and in phase II trials for osteoarthritis, severe and chronic pain, and acute pain and pruitus. Conventional morphine, fentanyl and hydromorphine opioids activate the central nervous system to relieve pain and find their way into the brain with unintended consequences. Difelikefalin targets the kappa opioid receptors in nerves outside the brain with more patient-friendly effects. In 2018, the company announced positive top-line phase II/III data from in patients undergoing abdominal surgeries. Difelikefalin demonstrated statistically significant reductions in pain intensity compared to placebo for periods of up to 24 hours. Additionally, treatment resulted in statistically significant reductions in the incidence of post-operative nausea and vomiting. Both doses tested exhibited trends toward reduced use of rescue analgesic medication compared to placebo, but the 0.5 mg/kg dose did not achieve statistical significance. In data from patients with osteoarthritis of the hip or knee, phase II data showed a mean pain intensity score reduction of 35% in all patients, which were statistically significant compared to placebo. Difelikefalin was tolerable with common adverse effects of constipation and dry mouth.

Other developments; including unique mechanisms of action

Currently in phase III trials for chronic pain is GRT 6005 (cebranopadol) under development by Grünenthal and Depomed (now Assertio Therapeutics). This has a unique mechanism of action as an opioid, binding to and activating all four of the opioid receptors. Recent results from a phase II trial in post-operative pain showed that single cebranopadol doses induced more effective analgesia following bunionectomy compared to the traditional opioid morphine, while cebranopadol and morphine ensured adequate 24-hour pain relief. Moreover, cebranopadol was better tolerated and received a better overall rating by the patients².

Also in phase III is SP 102, a non-opioid epidural steroid injectable which is being tested in the Phase III CLEAR trial to treat Lumbar Radicular pain/Sciatica. It is under development by Sorrento Therapeutics via its subsidiary Scilex Therapeutics.  

Cannabis to treat cancer pain

In February 2018 Tetra Biopharma  received a No Objection Letter from Health Canada to start its  landmark, 946 subjects, Phase III trial of PPP 001 ( delta 9 –tetrahydrocannabinol + cannabidiol) , a dried cannabis pellet designed  to be smoked in an inhalation device to treat pain in terminal cancer patients. Tetra has a number of cannabis products in development including Camuz (cannabis oil capsules) which recently entered the SERENITY trial to treat cancer pain. This trial followed a successful Phase II trial in March 2019. Tetra will now develop a version of this drug with a vaporiser which will be more acceptable to hospitals and palliative care centres.

NEXT TIME: We’ll be looking at some of the longer term prospects including compounds which when has demonstrated pain relief in macaque monkeys, with less of the addictive side effects and fewer signs of painful withdrawal.

See the the other 3 parts of the Opioids discussion: Replacement therapies for opioid drugs in pain treatment, Opioids: the future and challenging the epidemic, Opioids - Over the horizon.

1. “With concerns over opioids, could novel receptors be useful?” Carissa Sorenson et al., Practical Pain Management, Volume 18, Issue #4 https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/concerns-over-opioids-could-novel-receptors-be-useful.
2. “Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain.” Scholz A et al., Pain Physician. 2018 May; 21(3):E193-E206.