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Can Non-Opioid Agonists Prevent Drug Abuse, and What Are the Risks?

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While opioid drugs, such as hydrocodone and oxycodone, are widely prescribed to treat moderate to severe pain, lawmakers and regulatory agencies both agree that this has led to an opioid abuse and overdose epidemic in the United States.

Between 2000 and 2014, the Centers for Disease Control (CDC) noted that over a half-million people died due to an overdose on narcotics, including morphine, prescription painkillers, and heroin. Roughly 78 Americans die every day due to opioid overdose.

To help people struggling with opioid addiction, replacement therapies, such as methadone and buprenorphine, have become very popular in the last several decades. However, these drugs are also opioids; methadone is a full opioid agonist, while buprenorphine is a partial opioid agonist. These medications act on the opioid receptors, much like other narcotics, although they do not induce the same euphoric high in people who have developed a tolerance to opioid drugs. Still, for some people struggling to overcome opioid addiction, replacement therapies can become a new target for drug abuse and addiction.

There are several other treatment options for both pain relief and overcoming opioid addiction. While these may not be effective in every scenario, they are still options to consider as the opioid abuse epidemic in the US continues to grow.

Non-Opioid Painkillers

There are several kinds of non-opioid medications that can be effective for pain relief, depending on the individual’s condition.

  • NSAIDs: The main form of non-opioid painkiller is the NSAID, or non-steroidal anti-inflammatory drug. These drugs are often sold over the counter, and include aspirin and acetaminophen. When sold as over-the-counter pain relievers, both acetaminophen and aspirin are sold in low doses; however, there are also prescription versions of both of these painkillers are available in higher doses, with the intention that the prescribing physician will monitor the patient for potential side effects.
  • SNRIs and tricyclic antidepressants: Some people with chronic pain benefit from taking low doses of SNRIs (serotonin-norepinephrine reuptake inhibitors) or tricyclic antidepressants, instead of opioid drugs. These medications act on the release and absorption of neurotransmitters like norepinephrine and serotonin, which can both elevate mood and change how the brain manages pain.
  • Anticonvulsants: Some types of chronic pain, such as diabetic neuropathy, postherpetic neuralgia, or central neuropathic pain, have been successfully managed using drugs approved to treat epilepsy.

For people who are concerned about opioid abuse, whether due to a personal or family history of addiction or other concerns, doctors may be able to find alternate treatment methods involving the above drugs.


A conversation about these concerns will also help prescribing doctor better monitor their patients for potential addictive or drug abuse patterns.


Non-Opioid Medications for Opioid Addiction Treatment

For people who want to overcome an addiction to opioid drugs, and who do not want to use methadone or buprenorphine as maintenance and tapering therapies, there are some other options available.

  • Opioid antagonists: Both naloxone and naltrexone are occasionally used in detox and rehabilitation for opioid addiction. Naltrexone is an injectable medication, which blocks opioid receptors in the brain so the person does not experience euphoria when they ingest central nervous system (CNS) depressants, such as alcohol or narcotics. Naltrexone is most often used as a prescription medication once a person has successfully detoxed, so if the person relapses and begins to abuse narcotics again, they will not experience any effect. Ideally, this helps the person learn to stop habits associated with drug abuse.

Naloxone is an opioid antagonist that temporarily binds to opioid receptors and kicks opiates out. The medication is more commonly used to reverse an opioid overdose long enough for emergency medical services to arrive and begin other life-saving treatments. However, the prescription brand name medication Suboxone, a combination of naloxone and the partial opioid agonist buprenorphine, is used as “abuse-proof” maintenance therapy.

Both of these medications are considered nonaddictive and have very few side effects.

  • Clonidine: This is a medication approved to treat high blood pressure, but it is sometimes used off-label in detox and rehabilitation settings, including for opioid addiction. Clonidine relieves some of the most intense withdrawal symptoms a person experiences when they detox from opioids, including diarrhea, vomiting, sleep problems, and anxiety. While it helps to reduce much of the impact of withdrawal symptoms, especially during the first two weeks where they might feel the most intense, clonidine does not completely relieve all symptoms. For some people, this may be less effective at preventing relapse.Clonidine is not approved specifically for opioid abuse or addiction treatment in the United States, but its role in this setting has been extensively studied in other countries. When followed by a prescription for naltrexone, many people experience success overcoming opioid addiction using this medication.
  • Kratom: While this drug is heralded as an opioid treatment option by some, its use is dangerous. Kratom is a plant-based supplement derived from a species related to the coffee plant. The supplement itself is technically legal in the United States, although the Drug Enforcement Administration (DEA) has moved to ban the substance several times due to its high potential for addiction and overdose. It is not specifically sold as an opioid addiction treatment, but many people in the US self-report that the plant substance has helped them manage symptoms of opioid withdrawal in a similar way to buprenorphine or morphine. People who use kratom insist it is not addictive, but there is very little literature to support this claim, and an increasing amount of literature supporting its addictive properties.

Risks of Non-Opioid Agonists

No medication is without side effects and potential risks. It is important for doctors and patients to have frank and detailed discussions about concerns around opioid drugs and treatments aimed to overcome opioid addiction. Different therapies work for different people. For people who wish to avoid or overcome addiction to narcotic drugs, there are several options that do not involve narcotics at all. Still, these medications also have risks that the person ingesting them should be aware of.

  • NSAIDs: The FDA issued a risk warning in 2005 that some NSAIDs, such as ibuprofen and naproxen, had been linked to an increased risk of heart attack. NSAIDs can also lead to liver damage if a person takes in excess of 4,000 mg per day regularly, which can occur because these ingredients are in many over-the-counter cold, flu, and headache medications. Additionally, NSAIDs are not effective to treat pain that is not related to inflammation of muscle or nerve tissues. For pain that is not related to inflammation, or for severe chronic pain, finding another type of painkiller will be more effective.
  • Antidepressants: Although antidepressants can treat some types of pain very effectively, they can change brain chemistry to elevate mood, which may cause a negative psychological reaction in people who do not have underlying depression or a mood disorder. They also take several days or weeks to become fully effective, which can be frustrating, and they interact with other medications.
  • Naloxone: In very high doses in people being treated for narcotic overdose, naloxone can potentially cause neurotransmitters like serotonin, dopamine, and norepinephrine to break down rapidly into catecholamine. Sudden flushing of these neurotransmitters can lead to pulmonary edema and cardiac arrhythmias. Although it is extremely rare, this is part of the reason naloxone is used to temporarily reverse opioid overdoses, and it is not a larger part of opioid addiction treatment.
  • Naltrexone: As a maintenance therapy, naltrexone can be effective at stopping a person from experiencing a high when they ingest narcotics, but it can cause some side effects. These include severe abdominal pain, chest pain, confusion, depression or mood disorder, anxiety, shortness of breath, tinnitus, and weight gain.
  • Clonidine: Like naltrexone, clonidine has some side effects that can make the recovery process more difficult. These include fatigue, nervousness or anxiety, depression, insomnia, headache, appetite changes, nightmares, weight gain, and muscle or joint pain. These may feel like withdrawal symptoms associated with opioid detox.

Benefits of Non-Opioid Agonists

For people who do not want the risk of becoming addicted to opioid drugs, it is important to know that there are other potential treatments for all kinds of pain. Whether the pain is moderate and expected to go away in a brief period of time or the pain is chronic and part of a long-term disease, there might be non-opioid options worth pursuing. Further research into these treatments and how they work could change prescribing practices around opioid painkillers and help to reduce the severity of the opioid epidemic in the US.

Those who are working to overcome opioid addiction also have options that are not opioid maintenance therapies. Medical detox followed by an evidence-based rehabilitation program is the recommended course of treatment for nearly all addictions. For people who want a faster, but still safe, process through detox and into rehabilitation programs, naltrexone, clonidine, or another medication may help the withdrawal and addiction treatment process. Use should be determined on a case-by-case basis in consultation with a physician.

About The Contributor
The editorial staff of Laguna Treatment Center is comprised of addiction content experts from American Addiction Centers. Our editors and medical reviewers have over a decade of cumulative experience in medical content editing and have reviewed... Read More