What non-opioid alternatives actually work?
The strongest evidence here supports nonsteroidal anti-inflammatory drugs (NSAIDs) for specific types of pain. In a review of multiple randomized controlled trials for kidney stone pain (acute renal colic), NSAIDs achieved greater pain reduction, less need for rescue medication, and fewer vomiting events compared to opioids [7]. After ureteroscopy (a common stone surgery), NSAIDs provided equivalent or better pain control than opioids, and most opioid-free pathways reported that fewer than 20% of patients needed any opioid rescue [7]. This is a clear, practical win: for kidney stone pain and after stone surgery, NSAIDs can replace opioids for most patients.
However, not all non-opioid options have held up under scrutiny. A 2021 commentary in the Medical Journal of Australia warned that cannabidiol (CBD) lacks evidence for relieving back pain, and that the rush to approve it mirrors the earlier overuse of opioids for chronic non-cancer pain [6]. The authors urge that access to new pain medicines should not outpace scientific proof, a lesson learned from the opioid crisis itself.
A small experimental study from Pakistan (36 male patients) found that physiotherapy helped 66% of opioid users during detox feel relief without analgesics, compared to 25% for placebo and 75% for standard painkillers [5]. While the sample is tiny, it hints that non-drug approaches like physiotherapy could reduce drug-seeking behavior in rehabilitation settings.
Can reducing opioids actually backfire?
A large 2023 study of 61,249 surgical patients at Massachusetts General Hospital found something surprising: giving more opioids during surgery was associated with less pain after surgery, fewer new chronic pain diagnoses at 3 months, fewer opioid prescriptions at 30, 90, and 180 days, and less new persistent opioid use [2]. In other words, optimizing opioid use in the operating room — not eliminating it — led to better long-term outcomes. This challenges the current trend of reducing intraoperative opioids and suggests that a one-size-fits-all reduction could unintentionally increase opioid dependence later.
This finding is reinforced by a 2022 study of 1.2 million privately insured adults, which showed that from 2012 to 2019, opioid prescribing dropped sharply (from 49.7% to 30.5% for chronic non-cancer pain, and from 86% to 78.7% for cancer pain), but non-opioid medication use stayed flat or rose only modestly [1]. The authors note that reductions in opioids outpaced increases in non-opioid alternatives, meaning patients may have been left with undertreated pain — exactly the scenario the surgical study warns about.
What about entirely new types of pain medicines?
A promising experimental approach involves dual enkephalinase inhibitors (DENKIs), which work by protecting the body's own natural painkillers (enkephalins) from being broken down [4]. This activates opioid receptors without the side effects of external opioids like morphine. In animal studies, DENKIs have shown safety and potential for treating acute opioid withdrawal and chronic pain, but they are not yet approved for humans [4]. The authors argue this could be a game-changer for opioid use disorders, but it remains in the research phase.
A 2022 review in Drug Discovery Today emphasizes the urgent need for nonaddictive opioids and non-opioid alternatives, noting that abuse-deterrent opioids have had limited success and may push users toward more dangerous illicit drugs [3]. The review calls for continued discovery of novel analgesics, but does not provide new clinical data.
About These Sources
This answer is built on 7 peer-reviewed studies — published from 2021 to 2023, 4 in Q1 journals, collectively cited 182 times — selected as the most relevant from 7 studies that passed quality screening, drawn from 36 papers retrieved from a database of over 500 million.
Sources used in this answer
Trends in opioid and non-opioid treatment for chronic non-cancer pain and cancer pain among privately insured adults in the United States, 2012–2019
In a large claims database study (2012-2019), opioid prescribing for chronic non-cancer pain dropped from 49.7% to 30.5% and for cancer pain from 86% to 78.7%, while non-opioid medication use remained flat or rose modestly, indicating that opioid reductions outpaced adoption of alternatives.
Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use
In a retrospective cohort of 61,249 surgical patients, higher intraoperative opioid doses were associated with lower postoperative pain, fewer new chronic pain diagnoses at 3 months, and less persistent opioid use, suggesting that reducing opioids during surgery may have unintended negative consequences.
Opioid epidemic and the urge to discover new treatment options
A review argues that abuse-deterrent opioids have limited effectiveness and may push users toward more dangerous illicit drugs, emphasizing the need for nonaddictive opioids and non-opioid alternatives for acute pain.
The inhibition of enkephalin catabolism by dual enkephalinase inhibitor: A novel possible therapeutic approach for opioid use disorders
Dual enkephalinase inhibitors (DENKIs) protect natural enkephalins from breakdown, activating opioid receptors without typical opioid side effects; they show promise as a novel analgesic and treatment for opioid withdrawal, but remain experimental.
Pain Management in Opioids Users without Use of Medicines
In a small study of 36 male opioid users undergoing detox, physiotherapy provided relief for 66% of patients (vs. 25% for placebo and 75% for analgesics), suggesting non-drug approaches can reduce drug-seeking behavior.
Lack of efficacy of cannabidiol for relieving back pain: time to re‐set expectations?
A commentary warns that cannabidiol (CBD) lacks evidence for relieving back pain, and that access to new pain medicines should not outpace scientific proof, drawing a parallel to the opioid overuse crisis.
Nonopioid Pain Management Pathways for Stone Disease
A review of opioid-sparing pathways for kidney stone disease found that NSAIDs provide superior pain relief and fewer side effects compared to opioids for acute renal colic, and that after stone surgery, most patients (over 80%) can achieve adequate pain control without opioids.