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9 Articles in Volume 13, Issue #5
Elvis Presley: Head Trauma, Autoimmunity, Pain, and Early Death
Traumatic Brain Injury: Treatment of Post-traumatic Headaches
Advances in Pharmacologic Pain Management of Juvenile Idiopathic Arthritis
Integrative Treatment Approaches for Juvenile Idiopathic Arthritis
How Changing Hydrocodone Scheduling Will Affect Pain Management
Editor's Memo: Interpreting Indications For Electromagnetic Therapy
Specimen Validity Testing
Can a Buprenorphine Transdermal System (Butrans) Be Used to Treat OUD?
Letters to the Editor: Testosterone, Ultra-high Dose Opioids

How Changing Hydrocodone Scheduling Will Affect Pain Management

Since the FDA changed hydrocodone combination products from a schedule III controlled substance to a schedule II, pain practitioners and their patients need to know their options.

The FDA has now officially rescheduled hydrocodone combination products from schedule III controlled substances to schedule II. After a decade of limited momentum, a  request came before the FDA advisory committee in 2008, with a decision to keep hydrocodone combination products as schedule III.1 On January 25, 2013, after 5 years, this came to the forefront again, with an FDA advisory committee voting 19 to 10 to reschedule hydrocodone combination products from III to II.

After a scientific review, FDA made the recommendation that DEA take this step in December 2013. "We concluded that hydrocodone combination products meet the criteria for control under Schedule II of the Controlled Substances Act, and we believe DEA’s new rule will help limit the risks of these potentially addictive but important pain-relieving products," noted Douglas C. Throckmorton, MD, Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research.3  Prescription opioid contributed to over 16,000 overdose deaths in the United States.4

According to the FDA, here are some of the key changes that will occur with the reclassification of hydrocodone from a Schedule III drug to a Schedule II drug:

  • If a patient needs additional medication, the prescriber must issue a new prescription. Phone–in refills for these products are no longer allowed.
  • In emergencies, small supplies can be authorized until a new prescription can be provided for the patient.
  • Patients will still have access to reasonable quantities of medication, generally up to a 30-day supply.
  • If a patient needs additional medication, the prescriber must issue a new prescription. Phone–in refills for these products are no longer allowed.
  • In emergencies, small supplies can be authorized until a new prescription can be provided for the patient.
  • Patients will still have access to reasonable quantities of medication, generally up to a 30-day supply.
- See more at: http://blogs.fda.gov/fdavoice/index.php/2014/10/re-scheduling-prescription-hydrocodone-combination-drug-products-an-important-step-toward-controlling-misuse-and-abuse/#sthash.y24tdnVy.dpuf

Products Affected

All available combination hydrocodone products will be affected by the change. A list of medications with the amount of hydrocodone and the combination medications is listed in Table 1.5-9

Alternatives to Consider

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of acute or chronic pain can provide a viable alternative to hydrocodone, but increasing usage of these agents comes with increased risks of gastrointestinal (GI) bleeds, gastroesophageal reflux disease, and fatalities (due to bleeding and renal toxicity). Given these limitations, NSAIDs may be used more appropriately to treat mild-to-moderate somatic pain and should not be considered the panacea to replace hydrocodone. As with opioids, different patients may or may not respond to the various available NSAIDs, and efficacy with one does not guarantee response or failure of another. This may lead to a lengthy period of subtherapeutic analgesia while clinicians attempt to find the NSAID that works best for the patient.

For patients who experience GI side effects from NSAIDs, treatment with antacids, H2 receptor blockers, or proton pump inhibitors (PPIs) is recommended. In certain cases, switching the NSAID to one that is more cyclo-oxygenase (COX)-2 specific, such as celecoxib (Celebrex), etodolac, or meloxicam, may be necessary.10 For chronic NSAID use, concomitant therapy with a PPI may be indicated for gastric ulcer prophylaxis. NSAIDs should be avoided in patients who have a history of gastric/duodenal ulcers, blood dyscrasias, anticoagulation therapy, cardiovascular disease, diabetes mellitus, hypertension, concomitant use of nephrotoxic medications, or renal impairment.

Tramadol is another option to consider for the treatment of acute or chronic pain. It comes in several formulations including tramadol 50 mg, tramadol/acetaminophen 37.5 mg/325 mg, and tramadol extended-release (ER) 100 mg, 200 mg, and 300 mg. The maximum recommended daily dose of tramadol is up to 400 mg per day, depending on the formulation. The medication and its metabolite desmethyltramadol work as agonists at the µ opioid receptor. In addition, they cause serotonin and norepinephrine reuptake inhibition, the latter of which contributes to the analgesic effect. It is important to note that the µ-receptor binding affinity of tramadol is 6,000 times less than that of morphine, so the opioid agonist activity only provides minimal benefit.11 It is metabolized primarily by cytochrome P450 (CYP) 2D6 (desmethyltramadol) and CYP3A4, but there are five important metabolites.12 Inhibitors or inducers of this medication may affect the analgesic and toxicity profile of this drug, the most concerning of which are serotonin syndrome and seizure. Both of these potential toxicities could be enhanced by concomitant serotonin-type antidepressants across all chemical and therapeutic classes, lithium, and several other drug classes that may affect serotonin (certain antipsychotics, triptans, etc). As with NSAIDs, tramadol has pharmacology that can result in a significant rise in blood pressure. Finally, compared to other "opioid agonists," tramadol is one of the most constipating agents.

Acetaminophen with codeine is a schedule III option for the treatment of acute pain. This medication is inferior to hydrocodone, however, because it has significant variability in action with respect to absorption and activation. Codeine requires metabolism to morphine to achieve analgesia; this is accomplished by the CYP2D6 isoenzyme, which is necessary for the conversion on first-pass metabolism through the gut. Another issue is that patients with different polymorphisms could be fast and slow metabolizers of codeine, depending on their ability to make CYP2D6. Fast metabolizers end up experiencing a lot of analgesia for the dose received and may have side effects because of this; slow metabolizers, on the other hand, may not experience any benefit from the codeine because conversion to the active form is absent or negligible. Also, certain medications commonly induce or inhibit CYP2D6 isoenzymes. The selective serotonin reuptake inhibitors, in particular, have varying potency to inhibit CYP2D6, thereby preventing the conversion of codeine to its active analgesic form of morphine.

Buprenorphine is a viable schedule III option for the management of chronic pain. It works as a partial agonist on the µ-1 receptor and as an antagonist on κ receptors. The FDA recognizes the buprenorphine patch (Butrans) for treatment of moderate-to-severe chronic pain. The patch is not recommended if the patient is receiving 80 mg of oral morphine equivalents due to risk of opioid withdrawal. Conversions from morphine equivalent to the Butrans patch may be found within the package insert.13 The patch is refillable and requires once weekly changes. After steady state is reached, it provides linear consistent serum levels, unlike any immediate-release opioids such as hydrocodone.14

Pentazocine is another schedule III choice that may be used to provide patients with analgesia; however, we warn against this option for various reasons. Pentazocine has agonist activity at the κ receptor and partial agonist activity at the µ receptor. This prescription is formulated in a tablet with naloxone or acetaminophen but not pentazocine alone, and it is available as injection. Naloxone was added to the formulation decades ago to prevent abuse by dissolving the product and injecting it. Pentazocine is a racemic mixture of dextro- and levopentazocine, each causing its own unique set of side effects. Levopentazocine is known to cause analgesia and side effects that are common among the opioid class, including nausea, constipation, and respiratory depression. Dextropentazocine is known for causing hallucinations, delusions, and panic.15 In addition, penatazocine may increase systolic blood pressure. This may lead to an increase in cardiac load, with adverse cardiovascular events.16 It is for these reasons that pentazocine has fallen out of favor for the treatment of pain.

Acetaminophen as a single agent is yet another alternative that may be considered for the treatment of pain. The exact mechanism of action for acetaminophen has not been elucidated, although studies suggest that the COX-3 enzyme may have a role in its analgesic effects.17 The use of acetaminophen generally is regarded as safe, although there is a risk of liver toxicity at high doses, as well as potential drug interactions with drugs metabolized via the liver. Patients and prescribers need to be cognizant that combining several products containing acetaminophen is an avoidable liability. This risk is compounded when patients self medicate with over-the-counter sleep aids and cough and cold products that may contain acetaminophen, leading to an unintentional overdose.18 Nephrotic syndrome is a risk following chronic acetaminophen use over many years.19 Acetaminophen is available in several strengths from pediatric to adult formulations that can be used depending on the patients' need for pain relief. It also is available in several dosage forms, including tablet, capsule, gelcap, oral liquid, injection, and suppository forms. Following a 2009 FDA panel decision, the maximum amount of acetaminophen in products is 3,000 mg per day.20,21

Federal Law

As it stands, hydrocodone combination products are considered Schedule II medications, by Drug Enforcement Administration (DEA) definition, have a higher abuse potential than scheduled III agents.22

Schedule II prescriptions include, but are not limited to, fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. A schedule II prescription needs to be dated and signed on the date prescribed. Schedule II prescriptions may need to be filled within a certain period of time, depending on the state. If the state has no specific law on the subject, then the supremacy clause takes effect, meaning that a schedule II prescription has no "fill by" date. If this is not the case and the prescription is sufficiently old, the pharmacist should call the prescriber to ensure that the patient still requires the prescription before filling it.23-29

Emergency schedule II prescriptions may be telephoned or faxed to a pharmacy. There is no maximum limit on the quantity that may be called into a pharmacy under federal law. The prescriber may call in an amount that is sufficient to treat the emergency. The prescriber must then provide a signed prescription within 7 days of the emergency prescription. If mailed, it must be postmarked within these 7 days of the emergency prescription. If no cover is received within 7 days of the emergency prescription, then it is the pharmacist's duty to report this to the DEA Diversion Field Office. Failure to do so may result in the pharmacist's emergency fill privileges for Schedule II prescriptions being revoked.

If a pharmacist does not dispense the full quantity of a schedule II prescription, the balance must be filled within 72 hours. Failure to complete the partially filled prescription within 72 hours forfeits the balance of the controlled substance prescription. If this happens, the pharmacist should notify the prescriber that the patient was unable to attain the full amount of the prescription. Partial fills may be appropriate and are an acceptable option for patients in a long-term care facility (LTCF) or for terminally ill patients. The pharmacists should note the reason for partial prescription fill on the prescription.

A facsimile prescription may be sent to a pharmacy for filling. If this is done to expedite filling, a signed prescription must be brought in by the patient. If this is done as an emergency supply, the prescriber needs to provide a cover within 7 days. A cover is not needed if the prescription is for use in home infusion, in an LTCF, or for hospice care, as certified under Medicare under Title XVII. Schedule II may not be transferred or refilled.30

Hydrocodone Liability 

Although combination hydrocodone products just became Schedule II, hydrocodone monotherapy (Zohydro) has always been a schedule II medication.31 The original distinction was drawn between the combination formulation and the pure drug for two reasons. First, it was believed that if you were to combine hydrocodone with these other medications, then the amount of hydrocodone that would be needed to achieve a therapeutic effect would be less, due to synergy. Acetaminophen or other ingredients such as ibuprofen would lead to a decreased dose needed for analgesia,32 and chlorpheniramine and decongestants would lead to a lower dose needed for use as an antitussive. This could, in turn, lead to a lowered risk for experiencing euphoria and also may discourage misuse because of "undesirable" side effects from the adjuvant agent.

The second reason hydrocodone combinations were initially scheduled lower is because it was believed that the secondary medication, such as belladonna alkaloids, would cause dysphoric reactions at higher dosages, thus making it less appealing to abuse.33 This could cause significant and possibly dangerous toxicities at higher dosages and should, theoretically, lead to less abuse or misuse. However, while this deterrent may work for someone who is opioid-naïve, or someone who is compliant with hydrocodone, it may not be a deterrent for someone with a history of substance abuse. People with a past history of alcohol, prescription, or illicit substance abuse or misuse may use these formulations at higher dosages despite the toxicities that occur secondary to their use. In fact, what is thought to be an "undesirable" side effect for the legitimate user might be quite "desirable" for the abuser. In the authors' experience, some abusers have indicated that they derived pleasure from the sedating antihistamines and/or atropine alkaloids combined with these products.

In 2009, Wilsey et al reported that hydrocodone/acetaminophen 30 mg/975 mg (equivalent to 3 Norco 10 mg) had the same abuse liability as morphine extended-release (ER) 15 mg.34 In 2003, Zacny et al reported no significant difference between hydrocodone/homatropine 20 mg/6 mg and morphine 40 mg in terms of abuse liability.34 Both of these medications also were shown to have similar incidences of the unpleasant effects. More recently, Wightman et al showed that hydrocodone/acetaminophen 20 mg/1,000 mg (equivalent to taking 2 Lortab 10 mg) had a similar rate of "likability" as morphine 40 mg.34 In another study, Walsh et al examined high-dose hydrocodone, oxycodone, and hydromorphone as single agents.31 The investigators found that there was no significant difference in abuse liability with hydrocodone 45 mg, oxycodone 40 mg, and hydromorphone 25 mg. With an abuse liability similar to other schedule II medications, it begs the question of whether or not hydrocodone was properly scheduled in the first place or if some of the schedule II medications could just as easily be treated as schedule IIIs. They concluded that the equianalgesic dosing for an opioid medication is not a good measure of abuse liability.35

New York State Led the Way

As of February 23, 2013, hydrocodone combination products in New York State (NYS) became schedule II controlled substances. Based on discussions with colleagues in NYS, it appears that hydrocodone sales have dropped off slightly at the time. Moreover, an interesting outcome is that many patients previously receiving hydrocodone with acetaminophen are now receiving codeine with acetaminophen instead. These prescriptions are generally for more than 100 tablets per month and have multiple refills on them, which was largely unseen prior to the schedule change.

In the authors' opinion, this law has resulted in replacing hydrocodone with an option that is inferior therapeutically due to reduced efficacy, worse side effect profile, higher incidence of drug interactions, and greater toxicity. The standard of care suggests that extended release analgesics be used when chronic opioid therapy is required. The place for a medication like hydrocodone should, therefore, most commonly be in the treatment of acute pain or incidental pain in chronic patients; this is not the case, because hydrocodone prescriptions are commonly written to be filled monthly. Many patients in NYS still seem to receive their hydrocodone each month, only now they have an extra trip to the doctor's office to pick up the prescription, or must rely on the hard copy prescription being mailed at least until such time that electronic ordering is allowable by federal regulation. The effect of rescheduling hydrocodone in NYS remains to be seen. Perhaps the federal government could use the results of a retrospective analysis tracking outcomes from rescheduling hydrocodone in NYS to make a more informed decision about changing hydrocodone schedule status nationally. But, for now, there is no scientific evidence to support or dispute the rescheduling of hydrocodone.

Last updated on: May 19, 2015
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