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OPIOID USE DISORDER















  • The half-life of methadone is highly variable, with a duration of anywhere from 8 to 59 hours
  • Opiate products that come in extended- and controlled-release versions may have longer durations of action that affect when withdrawal may occur
  • References [2,7]
OPIATE HALF-LIVES
During chronic use, withdrawal symptoms may begin after 1 - 2 half-lives
Drug Half-life (hours)
Buprenorphine 24 - 42
Codeine 3
Fentanyl 8 - 10
Heroin 3 - 5
Hydrocodone 4.5
Hydromorphone
(Dilaudid®)
2.3
Hydromorphone ER
(Exalgo ER®)
11
Meperidine
(Demerol®)
3 - 8
Methadone 22 - 24
Morphine 2 - 4
Morphine CR
(Kadian®)
11 - 13
Oxycodone IR 3.5 - 4
Oxycodone ER
(Oxycontin®)
4 - 5
Oxymorphone 7 - 10
Tramadol 6 - 8



  • If the opioid is taken only as prescribed, this item does not count toward a diagnosis of OUD
  • Reference [2]
DSM-5 Opiate Use Disorder Criteria
Opiate use disorder is diagnosed based on the presence (within the past 12 months) of the 11 symptoms detailed below. The severity of OUD is defined as follows:
  • Mild: 2 to 3 symptoms present
  • Moderate: 4 to 5 symptoms present
  • Severe: ≥ 6 symptoms present
  • Opioids are often taken in larger amounts or over a longer period of time than intended
  • There is a persistent desire or unsuccessful efforts to cut down or control opioid use
  • A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects
  • Craving or a strong desire to use opioids
  • Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home
  • Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids
  • Important social, occupational, or recreational activities are given up or reduced because of opioid use
  • Recurrent opioid use in situations in which it is physically hazardous
  • Continued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids
Tolerance, as defined by either of the following:
  • A need for markedly increased amounts of opioids to achieve intoxication or desired effect
  • Markedly diminished effect with continued use of the same amount of an opioid
Withdrawal, as manifested by either of the following:
  • The characteristic opioid withdrawal syndrome
  • The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms











  • References [2,7]
Buprenorphine
Pharmacology
  • Buprenorphine is a partial opioid mu receptor agonist, which means it stimulates opioid receptors to a degree, but unlike full agonists, it has a ceiling effect. Buprenorphine binds opioid receptors tightly and disassociates slowly; this can cause it to displace full agonists (e.g. heroin, morphine) from the receptors and precipitate withdrawal. When absorbed intestinally, buprenorphine is rapidly metabolized in the liver via the first-pass effect. Because of this, it is only available in sublingual and buccal forms.

Pharmacokinetics
  • Onset of action: peak effect in 100 minutes
  • Half-life: 24 - 42 hours

Prescribing requirements
  • Providers must obtain a waiver and, in some cases, undergo special training in order to prescribe buprenorphine for OUD. See SAMHSA website for details

Prescribing documents
  • Several documents that may be helpful for buprenorphine prescribing are provided below
  • The PCSS also publishes buprenorphine prescribing documents. See PCSS clinical tools for more.

Dosage forms
  • There are 3 buprenorphine products used for acute opiate withdrawal - Subutex, Suboxone, and Zubsolv. Subutex contains buprenorphine, while Suboxone and Zubsolv contain buprenorphine and naloxone. Naloxone is included to deter injection of the product.

Choosing a product
  • For patients who are withdrawing from short-acting opioids, a buprenorphine/naloxone product is recommended for both withdrawal and maintenance treatment. Naloxone is included to deter injection because it will precipitate withdrawal when given parenterally. If the product is taken as instructed, naloxone-induced withdrawal is uncommon. However, if a patient is withdrawing from a long-acting opiate like methadone, naloxone-induced withdrawal may occur with sublingual/buccal administration. Because of this, buprenorphine-only products (Subutex) may be considered initially in these patients. After the patient is stable, therapy should be switched to a buprenorphine/naloxone product.

Naloxone (nasal spray or injection)
  • It is strongly recommended that all patients being treated for OUD be prescribed naloxone nasal spray or injection for emergency use (see naloxone below)

Switching between products
  • When switching between Subutex, Suboxone SL tablet, and Suboxone SL/buccal film, the buprenorphine dose remains the same; however, some patients may require dose adjustments after switching. Conversions for Zubsolv to other products are provided here - Zubsolv conversions.

Dosing
  • NOTE: all dosing is presented as buprenorphine with either Subutex or Suboxone
  • Timing of initial dose
    • Buprenorphine, a partial mu opioid receptor agonist, has the potential to displace full opioid agonists from opiate receptors and precipitate withdrawal. Because of this, it should not be administered too soon after the last opioid use.
    • In general, buprenorphine should be started 6 - 12 hours after the last use of heroin or other short-acting opioids and 24 - 72 hours after using a long-acting opioid like methadone (see opiate half-lives). Patients transitioning from methadone to buprenorphine should have their methadone dose tapered to 30 mg or less for at least 1 week before starting buprenorphine.
    • Opiate withdrawal assessment tools (see COWS and SOWS) can also be used to help time initiation. A COWS or SOWS score of ≥ 11 indicates that it is appropriate to start buprenorphine.
  • First day
    • An initial dose of 2 - 4 mg should be given. If the initial dose is well-tolerated, additional doses of 2 - 4 mg can be given at 2 hour intervals up to a total daily dose of 8 mg.
  • Second day
    • A single daily dose of up to 16 mg is recommended
  • Third day and on
    • The dose can be adjusted in 2 - 4 mg increments up to a total daily dose of 24 mg, with a recommended target dose of 8 - 16 mg once daily. Doses above 24 mg/day have not been shown to provide any further benefit.

Length of therapy
  • There is no recommended length of therapy for buprenorphine. Patients should be treated for as long as needed to maintain a stable, healthy life. Some patients may discontinue therapy after their withdrawal is over, while others may remain on buprenorphine for years. In general, treatment for less than 90 days has been found to be less effective than more prolonged therapy.

Discontinuing therapy
  • When a decision is made to discontinue therapy, buprenorphine should be gradually tapered to prevent withdrawal. See opioid tapering for recommendations on discontinuing therapy.
  • References [2,7]
Methadone
Pharmacology
  • Methadone is a full opioid agonist. Compared to short-acting opioids, it has a slow onset of action and long duration of effect, which helps to reduce the highs (euphoria) and lows (withdrawal) of opiate abuse.

Pharmacokinetics
  • Onset of action: peak plasma concentrations in 1 to 7.5 hours
  • Half-life: 22 - 24 hours on average; up to 59 hours in some people

Dosage forms
  • Tablet: 5 and 10 mg
  • Dispersible tablet for suspension (Methadose): 40 mg
  • Solution: 5 mg/5 ml, 10 mg/5 ml
  • Concentrate: 10 mg/1 ml
  • See methadone

Prescribing requirements
  • Methadone for OUD is available through clinics that have been accredited and certified by SAMHSA as opioid treatment programs. See SAMHSA website for details.

Naloxone
  • It is strongly recommended that all patients being treated for OUD be prescribed naloxone nasal spray or injection for emergency use (see naloxone below)

Dosing
  • Timing of initial dose
    • Methadone should be started when the patient is experiencing withdrawal symptoms and has no signs of intoxication or sedation
  • First day
    • The recommended initial dose is 10 - 30 mg. For individuals with no or low opioid tolerance (e.g. patients transitioning from naltrexone, patients re-entering the community after residential treatment or incarceration [with no agonist treatment], patients re-initiating methadone after relapse, no opiate use in the past 5 days), use a lower initial dose of 2.5 to 10 mg. Reassess patient in 2 - 4 hours and provide an additional 5 - 10 mg if the patient is still experiencing withdrawal. Do not exceed a total daily dose of 40 mg.
  • Second day and on
    • It's important to consider methadone's long half-life when titrating therapy. Daily dosage increases can cause drug accumulation several days later that raise the risk of oversedation. In general, methadone should be increased by no more than 10 mg every 5 days or 5 mg every 2 - 3 days. Effective maintenance doses are usually in the range of 60 - 120 mg/day.

Length of therapy
  • There is no recommended length of therapy for methadone. Patients should be treated for as long as needed to maintain a stable, healthy life. Some patients may discontinue therapy after their withdrawal is over, while others may remain on methadone for years. In general, treatment for less than 90 days has been found to be less effective than more prolonged therapy. For most patients, a minimum of 12 months of therapy is recommended.

Discontinuing therapy
  • When a decision is made to discontinue therapy, methadone should be gradually tapered to prevent withdrawal. See opioid tapering for recommendations on discontinuing therapy.

  • Reference [5,6]
Symptomatic Treatment of Opiate Withdrawal
Autonomic overactivity (elevated pulse and blood pressure, anxiety, chills, piloerection)
  • Clonidine
    • Clonidine is an alpha-2-agonist that is primarily used to treat hypertension. It works by suppressing sympathetic outflow from the CNS and is therefore useful in treating symptoms of opiate withdrawal.
    • Inpatient setting: starting dose is 0.1 - 0.2 mg every 4 - 8 hours with a maximum dose of 1 mg/day. Hold dose for SBP < 90 mmHg or DBP < 60 mmHg. On day 5, start to decrease dose by 0.2 mg/day. The average duration of treatment is 15 days.
    • Outpatient setting: doses of 0.1 - 0.2 mg two to four times a day are typically used. Blood pressure monitoring is recommended.

  • Lofexidine (Lucemyra®)
    • Lofexidine is an alpha-2 agonist that was FDA-approved to treat opiate withdrawal in 2018. Unlike clonidine, it does not have a generic and is very expensive.
    • Dosing: Three 0.18 mg tablets four times daily during the period of peak withdrawal symptoms. There should be 5 to 6 hours between each dose. Reduce dose over 2 - 4 days (e.g. reduce 1 tablet per dose every 1 - 2 days)
    • See Lucemyra PI for full prescribing information

  • Alternative therapies
    • Baclofen 5 mg three times daily. May increase to 40 mg/day. Re-evaluate in 3 to 7 days. The average duration of treatment is 15 days. May continue after acute withdrawal to help decrease cravings. Taper drug when discontinuing.
    • Gabapentin - start with 100 - 300 mg and titrate to 1800 - 2100 mg/day divided into 2 to 3 doses. It can help reduce withdrawal symptoms and help with pain, anxiety, and sleep.
    • Tizanidine 4 mg three times daily. May increase to 8 mg three times daily.
Insomnia
Anxiety
  • Diazepam 2 - 10 mg every 4 hours as needed | Maximum of 20 mg/day
  • Hydroxyzine 25 - 50 mg three times daily as needed
Lacrimation, rhinorrhea
  • Hydroxyzine 25 - 50 mg three times daily as needed
  • Diphenhydramine 25 mg every 6 hours as needed
Diarrhea
  • Loperamide (Imodium®) 4 mg initially followed by 2 mg as needed for loose stools; maximum of 16 mg/day
Joint pain, body aches
  • Naprosyn 500 mg twice daily as needed
  • Ibuprofen 800 mg three times a day as needed
  • Acetaminophen 650 mg every 6 hours as needed
Nausea and vomiting
  • Ondansetron (Zofran®) 8 mg every 8 hours as needed
  • Prochlorperazine (Compazine®) 5 - 10 mg by mouth every 4 hours as needed | Daily doses > 40 mg should only be used in severe cases
  • Promethazine 25 mg oral/rectal every 6 hours as needed
Abdominal cramping
  • Dicyclomine 20 mg every 6 - 8 hours as needed





















  • In general, drugs are detectable in the urine for 1 - 3 days after single-use, while chronic daily users may have detectable levels for longer periods
  • Reference [8,9,14]
UDS interpretation
Amphetamines
  • Detectable in urine for 48 hours
  • Standard immunoassays detect amphetamine, a metabolite of methamphetamine
  • Some ADHD drugs contain amphetamine (e.g. Adderall)
  • Part of standard workplace screen
Barbiturates
  • Short-acting barbiturates (e.g. pentobarbital) is detectable in urine for 24 hours
  • Long-acting barbiturates (e.g. phenobarbital) is detectable in urine for up to 3 weeks
Benzodiazepines
  • Short-acting benzos (e.g. lorazepam) are detectable in urine for 3 days
  • Long-acting benzos (e.g. diazepam) are detectable in urine for up to 30 days
  • Immunoassays may not detect benzodiazepines when they are used at therapeutic doses
  • Some tests have low sensitivity for clonazepam and lorazepam
  • More sensitive testing (e.g. chromatography) may be required to confirm negative results
  • Certain benzodiazepines are metabolized to other benzodiazepines, so confirmation testing may show multiple benzos when only one was consumed. For example, chlordiazepoxide and diazepam are both metabolized to temazepam and oxazepam.
Buprenorphine
  • Detectable in urine for 4 - 10 days
  • Buprenorphine is metabolized to norbuprenorphine, which is usually present in greater concentrations. Urinary immunoassays only detect buprenorphine and not norbuprenorphine. Patients can place a small amount of buprenorphine in their sample, and it will make it positive for buprenorphine. Confirmatory testing (chromatography/spectrometry) will detect buprenorphine and norbuprenorphine. A sample that contains a ratio of norbuprenorphine to buprenorphine of < 0.02 suggests that it was tampered with by adding buprenorphine directly to the urine.
  • Does not cause a positive opiate test. Must be detected separately
Cannabinoids
  • Single use is detectable in the urine for 3 days. Chronic use may be detectable for up to 30 days.
  • Detects the THC metabolite THC-9-carboxylic acid (THC-COOH)
  • Part of standard workplace screen
Cocaine
  • Detectable in urine for 2 - 4 days
  • Detects the cocaine metabolite benzoylecgonine (BZE)
  • Test is very sensitive and specific
  • Part of standard workplace screen
Ethanol
  • Only detectable for 10 - 12 hours after consumption
  • Ethanol metabolites ethyl glucuronide and ethyl sulfate are detectable for up to 5 days but must be ordered separately
Fentanyl
  • Detectable in urine for 1 - 2 days
  • Does not cause a positive opiate test. Must be detected separately
Heroin
  • Detectable in urine for 1 - 3 days
  • Identified by its metabolite 6-Monoacetylmorphine (6-MAM)
  • Causes a positive opiate result
Methadone
  • Detectable for 3 - 11 days with maintenance dosing
  • Does not cause a positive opiate test. Must be detected separately.
MDMA
  • Detectable in urine for 1 - 3 days
  • Methylenedioxymethamphetamine (Ecstasy)
  • False positives from trazodone and bupropion have been reported
Opiates
  • Detectable in urine for 2 - 4 days
  • Morphine, codeine, heroin, hydrocodone, and hydromorphone cause a positive result
  • Meperidine, methadone, buprenorphine, and fentanyl do not cause a positive result
  • Oxycodone and oxymorphone cause a positive result 1 - 10% of the time
  • Poppy seeds contain codeine and morphine and may cause a false-positive result. Most immunoassays use cutoff values that prevent positive results from poppy seed consumption. On confirmation testing, codeine and morphine values > 2000 ng/ml are consistent with opioid use as opposed to poppy seed consumption.
  • Part of standard workplace screen
Oxycodone
  • Detectable in urine for 2 - 4 days
  • Causes a positive opiate test 1 - 10% of the time
  • Detected with a separate test
Phencyclidine (PCP)
  • Detectable in urine for up to 8 days
  • Part of standard workplace screen



  • Reference [11,15]
URINARY METABOLITES OF OPIATES
Opiate Urinary metabolite Comment
Codeine
  • Morphine
  • Hydrocodone (< 10%)
  • Norcodeine
  • Codeine is metabolized to morphine
Buprenorphine
  • Norbuprenorphine
  • Norbuprenorphine is not detectable with urine immunoassays
  • Must be detected with chromatography/spectrometry
Fentanyl
  • Norfentanyl
Heroin
  • 6-monoacetylmorphine
  • Morphine
  • Normorphine
  • Morphine may be the only metabolite detected after heroin use
Hydrocodone
  • Hydromorphone
  • Norhydrocodone
  • Dihydrocodeine
Hydromorphone
  • Hydromorphone-3-glucuronide
Meperidine
  • Normeperidine
Methadone
  • 2-Ethylidene-1
  • 5-dimethyl-3
  • 3-diphenylpyrrolidine
Morphine
  • Normorphine
  • Hydromorphone (< 10%)
  • Morphine-6-glucuronide
  • Morphine-3-glucuronide
  • Codeine is sometimes a contaminant of morphine during manufacturing
  • Codeine contamination is typically 0.04% - 0.5% of morphine concentrations
Oxycodone
  • Oxymorphone
  • Noroxycodone
  • Hydrocodone is sometimes a contaminant of oxycodone during manufacturing
  • Hydrocodone contamination is typically < 0.1% of oxycodone concentrations
Oxymorphone
  • Oxymorphone-3-glucuronide
  • 6-hydroxy-oxymorphone






  • Reference: Zubsolv PI
Suboxone / Zubsolv Conversion
Suboxone dose Zubsolv dose
2/0.5 mg 1.4/0.36 mg
4/1 mg 2.9/0.71 mg
8/2 mg 5.7/1.4 mg
12/3 mg 8.6/2.1 mg
16/4 mg 11.4/2.9 mg







  • Reference: Subutex PI
Buprenorphine side effects in a 4-week study
Side effect Subutex 16 mg
(N=103)
Placebo
(N=107)
Headache 29.1% 22.4%
Insomnia 21.4% 15.9%
Withdrawal syndrome 18.4% 37.4%
Pain 18.4% 18.7%
Nausea 13.6% 11.2%
Sweating 12.6% 10.3%
Pain Abdomen 11.7% 6.5%
Infection 11.7% 6.5%
Rhinitis 9.7% 13.1%
Chills 7.8% 7.5%
Pain Back 7.8% 11.2%
Constipation 7.8% 2.8%
Vomiting 7.8% 4.7%
Asthenia 4.9% 6.5%
Diarrhea 4.9% 15.0%
Vasodilation 3.9% 6.5%




















  • Reference [7]
Side effect Naltrexone 380 mg
(N=126)
Placebo
(N=124)
ALT increase 13% 6%
AST increase 10% 2%
GGT increase 7% 3%
Nasopharyngitis 7% 2%
Influenza 5% 4%
Insomnia 6% 1%
Hypertension 5% 3%
Injection site pain 5% 1%
Toothache 4% 2%
Headache 3% 2%















Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability