The list of Schedule I includes marijuana, heroin, and LSD. We will discuss only the one currently being used for pain medication.
There are forty-six states where all forms of medical marijuana are legal: (Anderson & Rees, 2023). This is a controversial moment in the history of Marijuana legalization by the states because the drug is still classified as Schedule I by the Federal government. The VA and Federal Bureau of Prisons do not allow marijuana for their patients. If they have marijuana show up on a drug test, they will be penalized (VA, 2022). There is currently no consensus on what or when a change might be made, as marijuana could be reclassified (rescheduled), or perhaps as it is legal for recreational use in many states, it might be decriminalized federally (Celeste & Thompson-Dudiak, 2021).
These medications/drugs have the strictest regulations when compared to other prescription drugs because they are the most likely to be abused, diverted, or addicting. They include hydromorphone, meperidine, methadone, morphine, and oxycodone.
Morphine is used to treat soft tissue pain but also has been used to treat arthritis when other medications have failed. It is initially supplied as an oral solution, 10 to 20 mg PO every 4 hours as needed. Titrate the dose as needed to achieve adequate analgesia.
Initially, tablets, 10 to 20 mg PO every 4 hours as needed. Titrate the dose to achieve adequate analgesia—IV solutions 2 to 10 mg IV every 4 hours as needed.
Embeda® a combination with naltrexone for the opioid naïve patient, 20 mg/0.8 mg PO every 24 hours. Titrate the dosage every 1 to 2 days as needed to control pain. Do not dose more frequently than every 12 hours. Extended-release forms of morphine, such as MS Contin, should only be used for opioid-tolerant patients accustomed to ingesting over 400mg/day. MS Contin should not be crushed or chewed as this, and concurrent alcohol use will disrupt the extended time release mechanisms. They are leading to overdose and potentially death. This medication is contraindicated in all forms in patients with GI obstruction or acute post-operative pain.
Morphine in selected forms should be used cautiously for patients with variable respiratory diseases such as COPD, obstructive asthma, hepatic or renal dysfunction, brain injury, increased intracranial pressure, or severe hypotension. Use with caution in the elderly, alcoholic, morbidly obese, Addison’s disease, seizure disorders, benign prostatic hyperplasia, debilitation, pancreatitis, and cardiovascular disease. With appropriate dosage titration, there is no maximum dose of morphine (PDR, n.d.). To discontinue long-acting morphine preparations, taper the dose by 25% to 50% every 2 to 4 days. Significant opioid withdrawal symptoms may indicate the need to pause or slow the taper.
Hydromorphone/Dilaudid is a semisynthetic, phenanthrene opioid agonist. For the treatment of persistent, severe pain that requires an extended treatment period with a daily opioid and for which alternative treatments are inadequate. Give 2 to 4 mg PO every 4 to 6 hours as needed, initially. Titrate the dose to achieve adequate analgesia. Administer doses around-the-clock for chronic pain. A supplemental dose of 5% to 15% of daily usage may be administered every 2 hours as needed. With appropriate dosage titration, there is no maximum dose of hydromorphone.
For use in moderate to severe hepatic or renal disease of hydromorphone, reduce the first dose to 50% and 75%, respectively. The longer the duration of previous opioid therapy, the longer the taper may take. Common tapers involve a dose reduction of 5% to 20% every four weeks; a faster taper may be appropriate for some patients. Significant opioid withdrawal symptoms may indicate the need to pause or slow the taper. Opioids may be stopped, if appropriate when taken less often than once daily. Advise patients that there is an increased risk for overdose on abrupt return to a previously prescribed higher dose; provide opioid overdose education and consider offering naloxone. Monitor patients closely for anxiety, depression, suicidal ideation, and opioid use disorder, and offer support and referral as needed (PDR, n.d.).
Fentanyl is supplied as a sublingual, transmucosal, and nasal spray, transdermal patches, sublingual tablets, buccal lozenge, transmucosal lozenge, intramuscular injections, transmucosal tablets, IV injections, and electrically controlled transdermal patch. Different preparations of fentanyl are not interchangeable from microgram to microgram, even if administered via the same route. With the most popular clinic-level form, the transdermal 72-hour patch, providers should use a conversion table from other opiates used in the previous 24 hours to MME's then convert to fentanyl micrograms per hour.
Patients may use short-acting opioid agonists for the first 24 hours after stopping all other opiates at fentanyl patch initiation. For titrating the dose upward, the first time, from the lowest dose used, wait for a total of 24 hours after initialization of the patch. After that, the provider should wait six days to increase further. If the patient uses 45 mg per day of extra short-acting morphine, consider increasing the fentanyl patch to 12.5 micrograms in fentanyl patches to reach optimal dosage. Some severe pain issues may require patches to be changed every 48 hours instead of 72 hours to maintain optimal pain coverage. Education should be performed regarding exposures to new or used patches by other adults, children, or pets, as 30 to 85% of fentanyl may still be available in the used patches due to the product formulation.
Fatalities have occurred from children applying used patches during play or ingesting them. Consider not allowing children to watch the application of patches. Disposal of used patches is done by folding the patch so that the adhesive ends are together and flushing it down the toilet, if you cannot use an acceptable drug take-back site. If ingested, it may be fatal for children or pets. Never cut patches to reduce dosage, as this exposes the medication, causing toxic levels to the person managing it. Patches may be covered with a “breathable” clear dressing or taped around the edges with skin-friendly medical tape to prevent accidental dislodgement. Patients should rotate areas to apply patches. Completely avoid using heat or heating pads on patches, as toxicity could result.
The fentanyl patch is meant for transdermal use. Any other use of this preparation could lead to overdose or death via decreased respiratory drive and fentanyl toxicity. There is no maximum dose of fentanyl in this form. Avoid using it in severe hepatic and renal impairment. Decrease the first dose by 50% in mild to moderate hepatic or renal impairment. Patients who have overdosed should be transported via EMS and hospitalized for observation (PDR, n.d.).
Hydrocodone/Apap is a semisynthetic opiate agonist and a non-salicylate analgesic. Hydrocodone and acetaminophen are synergistic hybrids. As with all opiates, use caution with patients suffering from any process or disease that predisposes them to CNS depression or other breathing issues such as COPD, obesity, acute or severe asthma, or cor-pulmonary. The usual dosages of hydrocodone/ acetaminophen can cause apnea and decrease respiration drive in this population. Consider nonopioid medications for these patients. Monitor patients carefully for decreased respiratory reserve due to altered breathing patterns in patients with impaired consciousness. Also, recent, or concurrent use of CYP 453A4 inhibitors can increase the respiratory depression effect due to increased serum blood levels available (PDR, n.d.).
Opioid use requires an experienced clinician knowledgeable about the use of opioids, including the use of extended-release and long-acting opioids and how to mitigate the associated risks. All opiates have similar side effect profiles. From most to least severe, they cause all the obvious symptoms of CNS depression, such as decreased level of consciousness, increased respiratory depression, nausea, vomiting, constipation, slow gastric transit, and dry mouth. Unfortunately, hormonal, and immunological dysfunction can happen with chronic use, physical dependence, tolerance, and rarely hyperalgesia. According to the American Gastroenterological Association, the most common side effect is constipation that results from opiate-induced changes in the stomach, the intestines (large and small), the rectum, anus, and anal sphincter tone, is different from the usual causes of constipation and require special attention with specific treatment (Sizar, 2022).
Due to decreased gastric transits, stool bulking agents are not recommended for opioid-induced constipation (Sizar et al., 2022). Just as Narcan is prescribed for an overdose at the time of opioid initiation, education regarding maintaining regular bowel movements by increased water intake, exercising, and using laxatives should also be performed (PDR, n.d.).
Schedule III drugs have a lower misuse and addiction potential than I and II. Medications in this category are often used for pain control or anesthesia. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Examples of Schedule III substances include ketamine, opioid analgesics in this schedule include products containing not more than 90 mg of codeine per dosage unit, and buprenorphine/naloxone oral film.
These drugs are considered to have less likelihood of dependence and abuse. Carisoprodol is a centrally acting skeletal muscle relaxant and salicylate analgesic.
Carisoprodol is used for musculoskeletal conditions such as muscle spasms. Carisoprodol has a mild anxiolytic effect. Maximum is two tablets PO 4 times daily. This is equivalent to 1,600 mg of carisoprodol and 2,600 mg of aspirin daily. Use it with caution in debilitated elderly patients. Limit to 2-3 weeks as it has not been studied for long periods and is usually given in acute muscle pain situations. Most side effects of these medications come from the aspirin portion due to increased blood thinning. Avoid opioid preparations, which may increase CNS depression (PDR, n.d.).
Tramadol is an opiate sometimes used for patients experiencing intractable pain because of its impact on peripheral pain pathways, partial inhibition of serotonin reuptake, and low affinity for opioid receptors. This is thought to result in less sedation, respiratory depression, and potential for tolerance; however, constipation can still be problematic because of anticholinergic adverse effects. Caution should be exercised in administering tramadol to epileptic patients because this drug is known to lower the seizure threshold. In addition, tramadol should not be combined with morphine, selective serotonin reuptake inhibitors, tricyclic antidepressants (TCAs), or anticonvulsants because it can precipitate serotonin syndrome. Doses may need to be reduced in patients with renal failure (PDR, nd.).
Medications containing codeine must have less than 200 mg of codeine per 100 mL (cough syrups). Tylenol #3® and Tylenol #4®. Tylenol #3® and Tylenol #4® are an oral combination of analgesics, which include an opioid agonist. The combination is available as a liquid of 120 mg of acetaminophen per 12 mg of codeine in five ml. Oral tablets of Tylenol #3® are 300 mg of acetaminophen per 15 mg of codeine. Tylenol #4 is 300 mg per 30 and 300 mg per 60 mg daily. This is commonly used for mild to moderate pain where opioids are appropriate. Over 60 mg of codeine and one dose is not considered beneficial and raises the side effects profile. Adults and seniors’ maximum dose are 4000 mg of acetaminophen with 360 mg of codeine for the tablets and the liquid. Codeine as an opiate has all the same side effects and adverse effects as other opioids. This medication may mistakenly be less protected from children, pets, or other adults because of the Tylenol® name. Tylenol #3 and Tylenol #4 are acetaminophen mixed with codeine. Acetaminophen alone should only be given during pregnancy if the benefit to the mother outweighs the risk to the baby. Codeine is not recommended during labor due to decreased CNS and decreased contractions. Opioids do cross the placenta and breast milk and will decrease CNS. Naloxone may be needed to reverse increased respiratory depression in neonates if the mother takes the medication regularly. Regular use during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS) at birth.
Patients with respiratory dysfunction should not use this medication. If patients have hepatic or severe renal disease, dosing should be altered by longer intervals between doses and reduced dosages. Consider the lowest dose for the shortest time needed, as with all controlled substances. Monitor these patients for hypotension, respiratory depression, and sedation. Remember to taper according to the amount taken and time used. There are many drug-to-drug interactions, the most notable being other opioids, benzodiazepines, and MAOIs. Review drug lists carefully before prescribing.
Tizanidine/Zanaflex, a Centrally acting muscle relaxant similar chemically to clonidine, works about as well as baclofen. Give 2 mg PO every 6 to 8 hours as needed up to a maximum of 6 mg in 24 hours, initially. You may increase the dose by 2 to 4 mg/dose every 1 to 4 days until a satisfactory reduction of muscle tone is achieved. Max: 36 mg/day. Single doses of more than 16 mg have not been studied. To discontinue, reduce the dose by 2 to 4 mg/day, particularly in persons who have been receiving high doses for long periods like 20 to 36 mg/day for nine weeks or more, or who are receiving concomitant opioids, to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia. Abrupt discontinuation of tizanidine may result in withdrawal adverse reactions, including rebound hypertension, tachycardia, and hypertonia. To minimize the risk of withdrawal, particularly in patients who have been receiving high doses for long periods like 20 to 28 mg/day for nine weeks or longer, or who may be on concomitant treatment with narcotics, decrease the dose slowly, 2 to 4 mg/day (PDR, n.d.).
Tizanidine causes dry mouth. It may cause orthostatic hypotension, especially in the elderly. Avoid tizanidine in hepatic dysfunction and use it cautiously in pregnancy. It may be secreted in breast milk because it is lipid-soluble (PDR, n.d.).
Cyclobenzaprine/ Flexeril-a muscle relaxant for acute musculoskeletal pain, maximum dose of 10 mg three times a day after a start of 5 mg three times a day. PDR.net recommends two to three weeks as the maximum length of use. The extended-release product is 15 mg per day and is not recommended for the geriatric population due to the drug's substantial increase in plasma concentrations and half-life. A low dose of 1 to 4 mg at bedtime is being used for fibromyalgia patients’ sleep needs and pain reduction. However, evidence for this is weak. They may have cross hypersensitivity with TCA's as they are chemically related, and because they are cyclobenzaprine should not be used in patients with seizure disorders. It is not to be used for hyperthyroid patients due to the risk of cardiac events and depression, nor with MAOI. Serotonergic drugs tramadol, bupropion, SNRIs, meperidine, or Verapamil, may cause serotonin syndrome.
Interactions and adverse reactions are many, especially in a predisposed population such as patients with multiple comorbidities. It should not be used for intrathecal radiographic contrast administration; therefore, discontinue it 48 hours before and 24 hours after myelography. Patients should avoid prolonged UV exposure due to increased chances of sunburn. According to the Beers Criteria, cyclobenzaprine is an inappropriate medication for seniors due to strong anticholinergic activity and an almost twofold increase of plasma concentration in the elderly. This leads to weakness, sedation, and falls.
Side effects are many, usually noted early in treatment. Patients should be monitored for palpitations, confusion, and blurred vision. Later in administration, patients may see seizures, constipation, cardiac arrhythmias, and gastric and genital urinary symptoms. Rare but notable side effects could be NGO edema. Mild side effects such as xerostomia, drowsiness, dizziness, headache, GI disturbances, and fatigue may be seen. For more information online for this and all medications profiled here, go to www.pdr.net (PDR, n.d.).
Naloxone is an opioid antagonist, a derivative of oxymorphone employed for reversing the central nervous system and respiratory depression caused by opioid overdose.
Auto-injectors and nasal formulations are available to treat or prevent an overdose outside of the healthcare setting. Naloxone nasal insufflation may be used in adults, children, and even infants at both the 4 and 8mg doses.
Medicaid, Medicare, and most insurances cover Naloxone. There are free Naloxone programs nationwide and prescription cards that can reduce the costs of prescribed Naloxone to about $20.00 per kit. It should be remembered that as an opioid antagonist, it can precipitate a complete and sudden opioid withdrawal crisis for the patient. In the pain patient, too much Naloxone can also remove all analgesic effects of the opioid being reversed. This can be extremely dangerous, even fatal, for an opioid-addicted infant and extremely uncomfortable for the opioid-addicted in other age groups. Think severe instant withdrawal, a trip to the hospital to combat this may be necessary. The half-life of the nasal spray is comparable to the injection at about 2 hours. When given for fentanyl overdose, it may have to be repeated as fentanyl and other synthetic drugs, such as carfentanil related to fentanyl, are 10,000 times stronger than morphine. Naloxone should be used cautiously with patients taking buprenorphine and Cobistat concurrently with HIV protease inhibitors (PDR, 2023). As of this writing, Naloxone has been made an over-the-counter medication by the FDA.
Buprenorphine is prescribed for patient support while tapering off opioid addiction and can be combined with naloxone to make a medication called Suboxone®. Buprenorphine/naloxone combo is available dose is 2 to 8 mg tabs, taken twice daily. Babies born to mothers using opioids are likely to experience withdrawal with the combination drug. This medication is not low-priced at up to $350.00 a month and $450.00 a month as Suboxone® Medicare and Medicaid prices differ. It is a weaker pain medicine but cannot be combined with other opioid medications due to increased respiratory depression and changes in opioid metabolism. It may be used with NSAIDs, nerve blocks, regional anesthetics, and antiepileptics.
The provider must monitor for missed doses as they could be for illicit drug use. Monitor LFTs and warn patients that used as an IV drug damages the liver—considered safer at higher doses (24mg/day max) which may be required for off-label pain use. Compared to methadone, buprenorphine is safer and easier to wean a patient off 0f opioids than methadone. There are no special clinics needed. Methadone treatment is often lifelong, whereas suboxone treatment lasts 90 to 180 days. If combined with any CNS depressant respiratory depression may result (Pruess, 2022). Weekly meetings should be considered to reeducate family members on the signs and symptoms of toxicity and warn the patient not to mix with CNS depressants.
Medications with a strong CYP 450 dependent inhibitor, such as ketoconazole and protease inhibitors, may increase serum levels of buprenorphine. On the other hand, strong inducers of the enzyme, like barbiturates and some antiseizure medications, may decrease the levels of buprenorphine. Since the half-life is about 70 hours, it can be dosed every other day when a therapeutic serum level is reached. A long dry-out period is observed after methadone, fentanyl patch, long-acting morphine, or oxycodone preparation usage of up to 72 hours. With short-acting opioids like immediate-release oxycodone or heroin, just 6 to 12 hours is needed. To avoid sudden severe withdrawal symptoms from methadone, delay buprenorphine until the dose of methadone is decreased to 30 mg daily. Then a 72-hour dry-out is recommended. It does cross the placenta and is excreted in breast milk. It is a category C drug for pregnancy. The benefits are considered to outweigh the risk of opioid use during pregnancy. Specialized training is required to learn how to use buprenorphine effectively, maintain documentation, and patient monitoring. A DEA number is required to prescribe it (PDR, n.d.).
Methadone is structurally unrelated to morphine, and Methadone is a Schedule II synthetic opiate agonist. Used in medically supervised opiate withdrawal and maintenance programs; also effective for relieving severe or chronic pain. For the treatment of opiate dependence, prescribers must register and comply with the Narcotic Addict Treatment Act (NATA) [21USC 823(g)]. It is available as Methadone Hydrochloride/Methadone Oral Sol: 1mL, 10mg. This is the most commonly used form. With appropriate dosage titration, there is no maximum dose of methadone. Consider the loss of opioid tolerance for anyone who has not taken opioids for more than five days. With renal or hepatic dysfunction, start low and titrate slowly as metabolism is notoriously unstable. With mild to moderate renal function, a CrCl 30 to 50 mL/minute administer dosage every 6 to 8 hours. For a CrCl 10 to 30 mL/minute: Administer dosage every 8 to 12 hours. For a CrCl less than 10 mL/minute: Administer dosage every 12 to 24 hours.
Methadone is well known for “stacking up” in the elderly, meaning the metabolism is reduced and the prolonged half-life merges to the point that the dosages may overlap, causing an overdose. Monitor them closely for CNS depression. In case of an overdose, naloxone should be administered. Because methadone has a long half-life, it is necessary to provide a prolonged infusion or multiple doses of naloxone. Patients who have overdosed should be transported via EMS and hospitalized for observation (PDR, n.d.).
Flumazenil/ Romazicon Is not available commercially in an intranasal spray. Therefore, the overdosed patient must be transported immediately to the hospital for care. It treats benzodiazepine overdose, reverses benzodiazepine-induced sedation, and antagonizes the actions of zolpidem. It does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants. The initial dose is 0.2 mg IV. The dose may be repeated after 45 seconds if the desired level of consciousness is not achieved and subsequently at 1-minute intervals until a maximum of 4 doses have been administered. The dose is 1 mg total over 5 minutes. Observe the patient for at least two hours after administration for signs of re-sedation and hypoventilation. Repeat the regimen at 20-minute intervals, up to a maximum of 3 mg/hour. If this occurs, up to a maximum of 5 mg IV total cumulative doses for suspected benzodiazepine overdose. If the patient continues to be unresponsive at this dose, the cause of sedation is not likely to be benzodiazepines. The maximum dose for reversal of conscious sedation is 1 mg IV (PDR, n.d.).