In this discussion, we go over a quick review of opioids, drugs of abuse, opioid use disorder treatment, and naloxone administration.
Quick Review of Opioid Receptors
They assist with pain modulation, reinforcement and reward modulation, stress modulation, respiratory depression, immune system activation, and somnolence.
There are four opioid receptors. The main ones are mu, kappa, and delta. Remember that a full agonist generally has full binding agonist, and a partial agonist has high affinity, but low activity.
Opioid Epidemic
In 2019, there were over 70,000 deaths due to drug overdose. Interestingly, heroin use isn’t going up, but heroin death is going. This is probably due to a combination of use with other illicit drugs.
The opioid epidemic is usually thought of in three waves.
The first wave was in 1999 when there is a rise in prescription opioid use.
The second wave was in 2010 when there was a rise in heroin overdose death.
The third and most recent wave was in 2013 when synthetic opioids became available. These agents are more efficacious and result in more death.
Chronic Pain
Chronic pain is typically pain that lasts longer than 3 months. This pain should not be due to active tissue injury, but this can be hard to differentiate. It is important to realize that pain is highly influenced by psychological processing. In other words, pain is the perception of pain and can be affected by the mental state of the patient. Given this, pain may also be improved by psychological treatment as well.
It is thought that over 10-20% of the population is affected by this, and it is most likely under-reported.
Opioid use in chronic pain is very common. In fact, it is the mainstay of treatment for cancer pain. Efficacy in more common pain, such as back pain, is questionable. Some studies show that opioids are no anymore effective in pain reduction compared to simple analgesics like ibuprofen. Because of this, non-pharmacologic and non-opioid therapies are preferred, and if opioids must be used, multimodal therapy is preferred.
Opioids may be appropriate in certain scenarios, such as in patients with renal, cardiovascular, and high bleeding risk, or in patients whose benefits are likely to outweigh the harms.
In patients who take opioids long-term, there is some evidence that, over time, their experience goes up and their pain threshold goes down. This makes their pain sharper and worse. This was probably due to immune system activation. This is also why pain during the withdrawal phase is bad.
Opioid Formulation
There are multiple opioid formulations: short-acting, long-acting, and abuse-deterrent.
The long-acting formulations are useful for patients with cancer pain, palliative care, and sickle cell pain. They should be reserved for these due to the risk of overdosing. Abuse-deterrent is not routinely recommended because they’re not that effective in stopping patients from abusing other illicit drugs, such as heroin.
It is useful to know how to convert the dosing between each opioid agent. Each of the opioids is assigned a morphine equivalency. In most cases, it is a straight conversion, but in some like methadone, the dosing can be complicated due to its pharmacokinetic properties. Buprenorphine doesn’t have solid evidence for equivalency just yet.
Opioid Adverse Effects
Immediate adverse effects: constipation, sedation, vomiting, nausea, urinary retention, sleep-disordered breathing
Long-term adverse effects: hypogonadism, increased risk of MI, and immunosuppression
Opioid Risk Factors:
Conditions that may increase risk: COPD, OSA, renal insufficiency, or hepatic insufficiency
Other factors: mental health disorders, TDD higher than 100 MME, ER/LA, genetics, or benzodiazepine use.
It is important that these agents are not typically safe for renal and hepatic impairments. There is currently no concrete dose adjustment recommendation because there is no fixed dosing for opioids (pain perception issue.)
There are still some that are ‘safer’ than others:
- Renal insufficiency: buprenorphine and fentanyl
- Hepatic insufficiency: hydromorphone or hydrocodone as long as they are monitored closely
The CDC 2022 Guideline for Prescribing Opioids for Chronic Pain
Please note that this guideline is not for active cancer, palliative care, or end-of-life care
The main difference between the 2016 version and the 2022 is that the 2016 was a lot more stringent on certain scenarios, such as cannot exceed more than 90 MME per day. This caused more downstream problems and raises up new concerns.
The goals remain the same: to improve safety and efficacy, to reduce risks, and to improve communication.
There are 12 total recommendations:
- Non-pharmacologic and non-opioid therapies are as effective as opioid therapies in acute pain
- Non-pharmacologic and non-opioid therapies are preferred in chronic pain
- If going to start opioid therapy, the treatment goal and exit strategy should be clearly defined and continue a multimodal approach.
- Immediate-release is preferred
- Lowest effective dose and avoid increasing the dose if the diminished return is expected
- Taper the dose down carefully and do not stop the therapy abruptly.
- Lowest dose and for shortest time: 3 days is sufficient for most cases
- Reassess in 1-4 months after initiation or dosage change. Reassess every 3 months once stable.
- Constant evaluation of risks and naloxone need
- Review PDMP
- Toxicology screen if needed
- Use extreme caution using benzodiazepines together with opioid
- Medication-assisted treatment (MAT)
Define: physical dependence, tolerance, intoxication, withdrawal, and harm reduction
- Physical dependence – The body’s adaptation to the abused substance that leads to a withdrawal syndrome upon discontinuation.
- Tolerance – The down-regulation of receptors after repeated exposure to the abused drug.
- Intoxication – the acute syndrome after individual exposure to the substance, including maladaptive behavior, which can lead to overdose.
- Withdrawal – a set of symptoms experienced as a result of discontinuation after prolonged and chronic use of the abused drug.
- Harm Reduction – Provide illicit drug users with education for safer drug use.
Treatment goal: reduction/cessation of opioid use, prevention of complications, and prevention of overdose deaths.
Opioid Intoxication
Common Adverse Effects: euphoria, dysphoria, lethargy, somnolence, impaired motor skills, pinpoint pupil, and itching
Overdose Symptoms: Decrease respiratory drive, loss of consciousness, and death
Acute Opioid Withdrawal
Just look at the adverse effects of intoxication and think of the opposite.
- Euphoria –> anxiety, irritability
- Lethargy –> Tremor
- Somnolence –> Restlessness and sweating
- Pinpoint pupil –> Dilated pupil
Also think about “watery” symptoms, such as lacrimation, rhinorrhea, vomiting, and diarrhea.
Generally, opioid withdrawal is not life-threatening unless the patient has other serious co-morbidities.
The clinical Opiate Withdrawal Scale (COWS) is used to assess the patient.
Onset and duration depend on whether the patient’s on short-acting or long-acting agents. In general:
- Short-acting opioids:
- Onset: 8-24 hours after the last dose
- Duration: 7-10 days
- Long-acting opioids:
- Onset: 36-72 hours after the last dose
- Duration: 2 weeks or longer
After withdrawal, patients are at risk for relapse, but they must be careful because they now have decreased opioid tolerance to opioids. If they attempt to use the same amount of opioids as before, they have a higher risk of overdosing.
Commonly Abused Drugs
It was reported that over 33% of opioid prescriptions are abused either by the patient or by family members, but deaths due to prescriptive opioids alone are decreasing. The overall death is going up due to combining usage with other illicit drugs.
The three most commonly abused drugs are methadone, heroin, and fentanyl.
Methadone
Methadone accounts for over 30% of opioid death despite only comprising 2% of the total prescription opioids in 2009.
Methadone is a unique pharmacokinetic profile. It has a long, unpredictable half-life, but the effect only last 3-8 hours, which increases the risk of overdose. The steady state is not achieved for 3-5 days. This is why methadone titration can only be adjusted every 5 days. Periodic ECG monitoring is recommended due to the risk of QTc prolongation.
Heroin
The chemical name of heroin is diacetylmorphine, which hydrolyzes to morphine. Typically, heroin is given intranasally, subcutaneously, intramuscularly, or intravenously. The oral formulation is not popular due to a less rapid onset. The half-life of heroin is about 8 hours, but this number decreases with repeated exposure.
Fentanyl
Fentanyl is very potent. It is 50-100 times more potent than morphine. It also binds very tightly to the receptors. In fact, it binds so tightly that naloxone can have trouble kicking it off the receptors, leading to less sensitivity to naloxone than other opioids.
Fentanyl is also lipophilic and stays in the system for a long time. This can increase the risk of overdose.
OTC Drugs
While it’s not the most abused, due to the ease of access, it is worthwhile to mention the two OTC drugs that have some abuse potential.
The first is dextromethorphan, which is an opioid analog. Despite the mechanism, it acts more like an NMDA analog, and the individual must take a large amount of dextromethorphan to get any semblance of opioid effects.
The second is loperamide, which is an intestinal mu agonist. This medication is even harder to abuse because it usually doesn’t cross the blood-brain barrier. To get an opioid-like effect, a large quantity must be consumed. The problem is this also increases the risk of QTc prolongation.
Pharmacotherapy of Opioid Use Disorder
All opioid use disorders should be done in a medication-assisted therapy format, which means that medications are used in combination with counseling and behavioral therapies. The purpose behind this is to prevent withdrawal, replace risky opioids with monitored opioids, blunt euphoric effects, and reduce cravings.
Methadone
Methadone is extremely effective. As mentioned before, it binds very tightly to the receptors. This helps eliminates withdrawals and cravings by blocking the effects of illicit opioids. Because it is also one of the medications that are highly abused, it can still create physical dependence. This is why the administration of methadone for the OUD treatment can be complicated.
There is a 5-day waiting period before any titration can be made. Each titration is about 5-10 mg. Typically, methadone is dispensed as a diluted liquid where each patient receives the same volume although the concentration may vary. Each patient is monitored for 3 hours for signs of toxicity (sedation) during initiation.
Before initiation, patients should be assessed for any drug-drug interaction and obtain a baseline QTc. Typically the starting dose is 20-30mg. If the patient still displays withdrawal symptoms, an additional 10mg may be administered.
The initial target is 60-80mg per day.
Once the patient achieves the initial target, the titration is done much more slowly with no more than 10mg per week.
While 20-30mg may attenuate withdrawal, it generally doesn’t help with craving. As such, a dose of 80-100mg/day is usually utilized with a max of 150mg/day.
In patients who are adhered to and are at a steady maintenance dose, a take-home dose can be used, but the patients would be required to adhere to a strict adherence schedule.
Methadone is highly regulated in the U.S. This is to prevent diversion and reduce overdose risk. Each program must be licensed if it plans on dosing methadone longer than 3 days. Each patient of the treatment center must have documentation of OUD for at least 1 year unless the patient is:
- Done methadone maintenance in the last 2 years
- Recently released from incarceration or hospitalization and have documented likelihood of relapse
- Pregnancy
Buprenorphine
Buprenorphine is a partial mu-opioid receptor agonist. It is often combined with naloxone. Due to its binding affinity, it helps significantly with pain control but also blunts the effects of other opioids. Its long half-life allows for less frequent dosing, and it’s generally safe for renal impairment. Buprenorphine can be used in hepatic insufficiency, but the dose must be adjusted.
It is more difficult to abuse due to the combination with naloxone and its poor bioavailability.
Buprenorphine is initiated during the early signs of withdrawal, typically 6-72 hours after the last dose. The starting dose is usually 2-4mg with an additional 2-4 mg every 1-2 hours if the withdrawal symptoms still persist. The SL tablet is placed under the tongue until dissolved. Water should be avoided during dosing.
During the maintenance phase, buprenorphine can be dosed with SL, subdermal implant, or extended-release SQ injection. The dose for day 1 is derived from the initial TDD from the initiation phase. This dose can still be adjusted by 4mg per day if needed. In general, most patients require at least 16mg per day. The patient should be followed up weekly until stable, then may reduce monitoring to monthly.
Buprenorphine subdermal implant consists of 4 implants in the inner side of the upper arm. They are inserted at least 12-24 hours after the last dose of SL buprenorphine. These implants last about 6 months before needing removal. It is important to note that some patients may still require supplement SL therapy.
Buprenorphine extended-release SQ injection comes under the brand Sublocade. The injection usually follows at least a 7-day period of 8-24mg SL buprenorphine. The injection is 300mg monthly for the first 2, before decreasing to 100mg monthly for maintenance. If the patient is not stable on the 100mg, clinicians may consider increasing the dose back to 300mg.
Suboxone: Buprenorphine/Naloxone
In combination, it is important to note that naloxone may precipitate withdrawal symptoms if the patient still has some opioids remaining in their system. The dosing is similar to buprenorphine. The starting dose begins at 2mg/0.5mg or 4 mg/1 mg. This can be titrated up to 8mg/2mg on day 1. On day 2, the dose can be titrated up even further to 16mg/4mg if needed. During the maintenance phase, the dose can be titrated up by 2mg/0.5mg at a time. The usual range is 2-24mg / 1-6 mg.
Zubsolv is another version of buprenorphine/naloxone. It has greater bioavailability compared to Suboxone.
Choosing a Buprenorphine Product
The reasons why buprenorphine/naloxone films are preferred are because they are fast absorbing, easy to cut (adjust dose), and have low abuse risk.
Zubsolv is reported to have a better taste and faster dissolve time.
Buprenorphine alone is preferred in pregnancy or concomitant pain.
Prior to starting the treatment, you should check PDMD, review for drug-drug interactions (HIV, BZDs, antidepressants), obtain a urine drug screen, and establish goals.
Naltrexone
Naltrexone takes a different approach to OUD treatment. It is a pure opioid antagonist. Interestingly, a tablet is likely no more effective than a placebo. This is probably due to poor adherence because it is hard to keep the motivation to keep taking the medication.
The extended-release IM formulation (Vivitrol) fixes the non-adherence problem and has proven to be a viable option for OUD. But, it is still not as effective as methadone or buprenorphine.
Patients should be challenged with naloxone first prior to the initiation, and patients need to be opioid-free for 7-10 days before. The starting dose is 380mg IM every 4 weeks. If the patient has breakthrough cravings, every 3 weeks regimen may be considered. The injection needs to be done with provided and into the gluteal muscle.
Adverse effects include mildly increased LFTs (transient) and opioid withdrawal within minutes.
This must be discontinued at least 30 days prior to surgery requiring opioid pain management.
The goals of MAT:
Substance use disorder is a chronic and recurrent condition. The relapse rate is over 50% post-MAT. This is why for some individuals, it is reasonable to continue the treatment indefinitely. For those who wish to stop MAT, it is recommended that the patient is stable for at least 6-12 months, and the patient must have a stable career and support system.
Naloxone – The Reversal
Naloxone is a pure opioid antagonist with very minimal oral bioavailability. Naloxone has been proven to reduce opioid-related deaths.
Naloxone is available in multiple formulations: IV, IM, SQ, intraosseous, and intranasal. The onset is quick (60 seconds for IV and 2-5 minutes for IM and intranasal) and the half-life is short.
Due to binding affinity, some opioids are less sensitive to naloxone. These are buprenorphine, fentanyl, and other synthetic opioids.
EMS should ALWAYS be contacted before or directly after the first dose of naloxone.
A second dose of naloxone should be administered in 2-3 minutes if no response from the first.
Pregnancy
Naloxone and extended-release naltrexone are not currently recommended for use during pregnancy.
It is important to use the lowest effective dose. A discussion with the patient is probably the most important part of the treatment.
Acute Opioid Withdrawal
There are multiple agents that can be used for acute opioid withdrawal.
- Buprenorphine: 4-8mg once
- Methadone: 20mg PO
- Clonidine: 0.1-0.3 every hour until no symptom. Not to exceed 0.8 typically, but a hard limit at 1.2mg
- Benzodiazepine
- Diazepam 10-20mg IV every 5-10 minutes
- Lorazepam
- Supportive care (promethazine)