Controlled Substances: A Prescribers Guide (FL INITIAL Autonomous Practice- Pharmacology)

Across the United States, mid-level providers are more commonly gaining authority to prescribe controlled substances. A controlled substance is a drug, compound, preparation, mixture, or substance contained in Schedule I, II, III, IV, or V. This list is updated annually and substances are put into their schedules based on the substances current medical use, abuse potential and likelihood of causing dependence when abused.

Controlled substances are laced with risks. Understanding the risks of controlled substances is critical for proper prescribing. The prescriber who understands the medications and how to prescribe them properly will provide better and safer care for their patients.

Prescription opioid abuse takes a heavy toll on the patient, health care provider and society. Abuse and misuse of controlled substances occurs for multiple reasons including: self-medication, use for reward, diversion for profit and compulsive use. The use of opioids has increased in recent times, leading to an increase in abuse and opioid overdoses. Proper screening will reduce the risk of iatrogenic addiction. Unfortunately, no currently available screening method accurately predicts who is at high risk to abuse or misuse opiates (Sehgal, Manchikanti, & Smith, 2012).

Using prescribed medications not as directed describes potentially aberrant drug-taking behaviors. In a study of 202 patients, only 44.1 percent were screened for potentially aberrant drug-taking behaviors. It was concluded that screening for abuse or misuse of opioids does not occur frequently in a large family medicine training program. More training and set policies for risk evaluation and monitoring for opioid abuse is needed (Lewis, Herndon, & Chibnall, 2012).

Prescriber lack of training and inexperience can have a profound impact on misuse of medications. In a recent study, resident physicians (when compared to attending physicians) more often prescribed opioids for more than three months, were more likely to have their patients report that their prescriptions were lost/stolen, were more likely to have patients who exhibited substance misuse and were more likely to have their patients get opioids prescribed by a different prescriber in addition to them (Colburn, Jasinski & Rastegar, 2012).

Prescribers receive little training in how to prescribe scheduled substances, how to screen for substance abuse and how to refer patients who need treatment for substance abuse. Proper continuing education is one way to address this problem (Brown, Swiggar, Dewey & Ghulyan, 2012).

• Pain An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (Merskey & Bogduk, 1994).   
• Acute pain that has an abrupt onset and offers a warning of a disease process or a threat to the body.   
• Chronic pain that lasts beyond the usual duration of time that an insult or injury to the body needs to heal. Pain without apparent biologic value that has lasted beyond the usual tissue healing time (typically at least three months). Some define chronic pain as pain that continues for at least six months (America Psychiatric Association, 2013).   
• Maladaptive pain that is not useful and is out of proportion to tissue damage. This type of pain tends to last long after tissue healing and is often due to changes in the central nervous system.   
• Adaptive pain that protects the individual from injury and aids with healing after an injury.   
• Allodynia pain from a stimulus that typically does not cause pain.   
• Hyperesthesia Increased sensitivity to stimulation.   
• Paresthesia An unusual sensation that is often described as burning or prickling and commonly affects the extremities.   
• Visceral pain from the viscera mediated by stretch receptors. This pain is commonly described as deep, dull, poorly localized and cramping.   
• Nociceptive pain from threatened or real tissue damage to non-neural tissue that is caused by the activation of nociceptors.   
• Neuropathic pain from abnormal neural activity from an injury, disease process or dysfunction of the nervous system.   
• Mononeuropathy - Neuropathy affecting one nerve.   
• Polyneuropathy Neuropathy affecting several nerves.

In 1970, section 812 of the Controlled Substance Act was enacted which lists substances that are controlled (Drug Enforcement Agency, 2014). The list describes basic or parent chemicals that may be classified as controlled substances. The Controlled Substance Act divides the drugs and other substances into five schedules, which is updated annually at (View Source).

Schedule I controlled substances have no accepted medical use in the United States, have a high potential for abuse and lack safety data. Substances in this class include: heroin, marijuana, 3, 4-methylenedioxymethamphetamine ("Ecstasy") and lysergic acid diethylamide (LSD).

Schedule II and IIN substances may potentially be abused and may lead to severe physical or psychological dependence. Schedule II narcotics includes: oxycodone (OxyContin, Percocet), fentanyl (Sublimaze, Duragesic), methadone (Dolophine), hydromorphone (Dilaudid), morphine, opium, and codeine. Examples of Schedule IIN stimulants include: methylphenidate (Ritalin) and amphetamine (Dexedrine, Adderall).

Schedule III or IIIN substances have less abuse potential than those substances that are Schedule I or II. They are high risk for psychological dependence and low to moderate risk of physical dependence. Examples of medications in this class include: buprenorphine (Suboxone) and products that have less than 90 milligrams of codeine per dosage unit such as Tylenol with Codeine. Medications that are considered Schedule IIIN include: anabolic steroids such as Depo-Testosterone and ketamine.

Schedule IV controlled substances have a lower potential for abuse when compared to Schedule III controlled substances. Examples of medications in this class include: benzodiazepines, midazolam (Versed), modafinil (Provigil) and carisoprodol (Soma).

Schedule V controlled substances have a low abuse potential relative to Schedule IV substances. Examples of medications in this class include cough preparations that contain less than 200 milligrams of codeine per 100 milliliters or per 100 grams such as Robitussin AC, lacosamide (Vimpat), and pregabalin (Lyrica).

The Controlled Substance Act regulates five classes of medications: anabolic steroids, depressants, hallucinogens, narcotics and stimulants. Each class has different properties and substances in each class typically produce similar effects. Most controlled substances alter mood, feeling or thought due to their effect on the central nervous system. Medications likely to produce euphoria are more likely to be abused, but medications may be abused to aid in sleep, reduce pain, reduce anxiety, reduce depression and improve energy.

Opioids have the potential to provide analgesia and improve function. These benefits must be weighed against the potential risks including: misuse, addiction, physical dependence, tolerance, overdose, abuse by others, drug-to-drug and drug-to-disease interactions.

Opioid misuse and abuse is a major public health problem and it affects 34.2 million Americans over the age of 12 (SAMHSA, 2012). According to the Center for Disease Control, in the United States, 46 people die each day from an overdose of prescription painkillers. In 2012, health care providers wrote 259 million prescriptions for painkillers (Center for Disease Control, 2014). Two times as many painkiller prescriptions are written in the United States as in Canada.

In addition to opioids, other medications are associated with misuse. These include: stimulants, sedatives, hypnotics and others. The use of stimulants has increased over recent years. Abuse is most common in those 18-25 years old. In the last year, 2-5 percent of high school students misused methylphenidate (Wilens, Adler, Adams, Sgambati, Rotrosen, Sawtelle, Utzinger, & Fusillo, 2008). Among college students, 5-6 percent misused stimulants in the last year and 5-43 percent misused stimulants over their life (Bogle & Smith, 2009).

Stimulants have the potential to cause tachycardia, high blood pressure, increased body temperature, reduced appetite, anxiety, reduce sleep, agitation and paranoia. Overdose of stimulants may lead to agitation, tremor, confusion, anxiety, delirium, mydriasis, hyperreflexia, aggressiveness, hallucinations, delirium, paranoia, seizures and movement disorders (Spiller, Hays, & Aleguas, 2013).

To prevent prescription drug abuse the clinician needs to assure:

•   Patients are assessed and reassessed   
•   Treatment agreements are used   
•   Prescription monitoring occurs
•   Safe prescription methods are practiced

Patients risk should be assessed and contraindications should be immediately identified. Contraindications to opioid treatment include those who have erratic follow up, suffer from current untreated addiction or have poorly controlled mental illness (Chou, Fanciullo, Fine, Adler, Ballantyne, Davies, Donovan, Fishbain, Foley, Fudin, Gilson, Kelter, Mauskop, O'Connor, Passik, Pasternak, Portenoy, Rich, Roberts, Todd, Miaskowski, American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel, 2009).

Chronic pain affects approximately 76.2 million Americans (National Centers for Health Statistics, 2006). Pain is a common problem seen in primary care with about 20% of outpatient visits being for pain issues (Alford, Liebschutz, & Chen, 2008). Chronic pain affects about one in two long-term care residents (American Medical Director Association, 2009).

Persistent pain is often associated with anxiety, depression, functional impairment, sleep disturbances, disability, and impairment in activities of daily living. Every year, chronic pain leads to more than 50 million lost work days in the United States and costs the American tax payer over 100 billion dollars (Stewart, Ricci & Chee, 2003).

Chronic pain is defined as pain lasting more than 3 months and may affect any part of the body. Chronic pain is most frequently caused by back pain (10%), leg/foot pain (7%), arm/hand pain (4.1%), headache (3.5%), and wide spread pain (3.6%). Many affected by chronic pain have more than one type of pain (Hardt, Jacobsen, & Goldberg, 2008).

Mental health and pain are connected as individuals with chronic pain often have a psychiatric co-morbid condition. Those with a combination of mental illness and chronic pain are more likely to misuse controlled substances. In order to adequately treat pain it is imperative to assess and manage mental illness. Those who have a mental health diagnosis are more likely to use opioid medications than individuals who do not have a mental health diagnosis (Closs & Briggs, 2002).

It is complex to differentiate between those who have primary psychopathology from individuals with psychological symptoms secondary to their pain. Mental health referral is often helpful to differentiate these factors and manage pain.

The management of pain may include: medications, behavioral interventions, physical medicine, neuromodulation, medical interventions or surgery. The use of a multidisciplinary approach is typically used in the management of chronic pain.

Current treatments to manage chronic pain result in approximately a 30 percent reduction in pain (Turk, Wilson, & Cahana, 2011). One of the problems is general physicians have limited training in the management of chronic pain (Institute of Medicine, 2011). The use of a pain management specialist is often needed to manage pain properly.

The World Health Organization (WHO) analgesic ladder was created for the management of cancer pain and published in the 1980s (World Health Organization, 2014). Key points of the analgesic ladder include:

• Medications are given though the most comfortable route (preferably orally).   
• Follow a stepwise approach and start with non-opioid medications with or without adjuvant medications.   
• Mild to moderate enduring or progressive pain should be managed with opioids, with or without adjuvant medications, with or without non-opioids.   
• For persistent pain or pain that is increasing notwithstanding the previous step, the use of more potent opioids such as morphine with or without adjuvant medications with or without non-opioids ought to be considered.   
• Analgesic pain medication used for moderate to severe chronic pain should be administered on a fixed schedule (not as needed).   
• This approach is 80-90 percent effective.

Adjunctive medications are used to enhance the analgesic effect, reduce side effects and assist with co-existent symptoms. Different patients will respond distinctively to different treatments in regard to efficacy and side effects. Trial and error is often used in the treatment of chronic pain.

When starting therapy, the dose should be initiated at a low dose and titrated to obtain pain control and minimize side effects. Tolerance often develops as a patient gets used to the medication.

Treatment is typically started with short-acting medication and the medication is titrated upwards to control pain while side effects are monitored. After determining the dose of the medication required to provide adequate pain relief with minimal side effects, the medication can then be converted to a sustained release form and be administered once or twice a day. When long-acting medication is used, breakthrough medication can be given.

While the patient is being treated for pain the clinician should assess and document the effect on functional status, pain control, intensity of pain and side effects.

Analgesic agents are often given orally as this is convenient and allows a relatively steady blood concentration of the drug. Pain medication may be administered on an as needed basis for episodic pain or it may be given routinely for chronic pain. The use of routine, around-the-clock medication sustains a steady state in the blood and offers better pain relief for those with persistent pain.

Classes of medications include: non-opioid analgesic agents, antidepressants, muscle relaxants, antiepileptic medications, topical agents, opioids, alpha 2 adrenergic agonists and N-methyl-d-aspartate (NMDA) receptor antagonists. Some get effective relief from one medication, but some get better pain relief from a combination of medications that work on different pathways. Unfortunately, research is sparse on combination medication in the management of pain.

Considering all co-morbidities is an important step in the management of pain. For example, when a patient is afflicted with chronic pain and depression some medications may help effectively manage both conditions (for example, duloxetine is approved to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain in addition to depression). It is also important to establish the pathophysiology of the pain syndrome, evaluate the medication list, and consider the side effects of the medications being prescribed.

The clinician should distinguish between neuropathic pain and nociceptive pain. The etiology of neuropathic pain must be established and if the etiology is reversible, manage the underlying problem. For example, if a medication (e. g., metronidazole, nitrofurantoin, isoniazid, or many cancer agents) is the etiology of the neuropathy stop that medication.

Medications used in the treatment of neuropathic pain include: calcium channel alpha 2-delta ligands (gabapentin and pregabalin), tricyclic antidepressants, serotonin norepinephrine uptake inhibitors (SNRIs), the lidocaine patch and narcotic analgesics.

Numerous non-pharmacologic therapies are used in the management of pain. Methods used other than medications include: physical therapy, exercise, massage, ultrasound therapy, heat/cold application, chiropractic manipulation, biofeedback, psychotherapy, relaxation therapy, acupuncture, transcutaneous electrical nerve stimulation (TENS), injections, neuromodulation, spinal cord stimulation, deep brain stimulation, and radiofrequency ablation of nerve tissue.

Anxiety is a condition commonly treated with controlled substances, specifically the benzodiazepines. Common anxiety disorders include: generalized anxiety disorder, panic disorder, social phobia and obsessive compulsive disorder. Anxiety affects 40 million Americans (Anxiety and Depression Association of America, 2013).

• Generalized anxiety disorder (GAD) affects 3.1% of Americans. Females are afflicted at a rate two times more commonly than men. Those with GAD often have co-morbid depression and are more likely to abuse alcohol and other substances (Fredman & Korn, 2002). Seven percent of patients in primary care are afflicted with generalized anxiety disorder (Seitz, 2005), with only 60 percent of these patients being treated (Healthy People 2010, 2014).   
• Social phobia affects 6.8% of the population and affects males and females equally.   
• Panic disorder affects 2.7% of the American population. Females are afflicted at a rate two times more commonly than males. Those with panic disorder are often affected with co-morbid depression.   
• Obsessive compulsive disorder affects approximately 1.0% of Americans with men and women being equally affected.   
• Post traumatic stress disorder affects approximately 3.5% of Americans with females being affected more commonly than males.

Attention deficit hyperactivity disorder (ADHD) is condition of distractibility and inattention. It may or may not be associated with hyperactivity. The pathology is ADHD is unknown, but it is theorized that certain parts of the brain linked to attention are lacking in neural transmission. The incidence of ADHD is 3-7 percent in school aged children and is more common in boys than in girls, but the inattentive type is more common in girls. Those with ADHD are at increased risk to have substance abuse problems. In adults, its prevalence is estimated at 2-7% (Sofeff, 2014).

There are three types of ADHD.

•   Predominantly hyperactive   
•   Predominantly inattentive   
•   Combined

The inattention type must have at minimum six symptoms of inattention persisting for at minimum six months to a point it is maladaptive and not consistent with the developmental level. These include: difficulty maintaining attention in play or tasks, forgetful in daily activities, avoids tasks/strongly dislikes tasks that require mental effort, easily distracted, loses items necessary for tasks or activities, does not seem to listen, difficulty organizing tasks and activities, fails to pay close attention to details or makes careless mistakes and does not follow through on instructions.

The hyperactive/impulsive type (Sofeff, 2014) must have at minimum four of the following symptoms for at minimum six months to a point it is maladaptive and not consistent with the developmental level. These include: hyperactive with difficulty playing or engaging in leisure activities quietly; fidgeting with feet and/or hands or squirming in the seat; running around, climbing excessively when it is inappropriate; impulsive with blurting out answers to questions prior to the question being asked; difficulty waiting in line or waiting for their turn in a group situation; and leaving the seat when the individual is expected to remain sitting.

Other features include (Sofeff, 2014): onset is not later than 7 years of age; symptoms present in two or more situations (e.g., work, home or school); these symptoms cause significant distress or impairment in academic, occupational, or social functioning; and symptoms are not better explained by another mental illness.

Prior to prescribing medications for ADHD the clinician must assure that the patient:

• Does not have a history of seizures, Tourette syndrome, significant anxiety or pervasive developmental delay   
• The child has a normal blood pressure and heart rate   
• The child is at least six years old   
• There is a complete diagnostic assessment that confirms ADHD   
• The parents accept medications as a method to manage the condition   
• The school is cooperative in monitoring and administering   
• No prior sensitivities are noted to the medication   
• No concern for substance abuse among those that live the with patient (particularly with immediate release stimulants)

Prescribing controlled substances is an important role the practitioner. Controlled substances are laced with risks and it is important for the prescriber to realize that a primary goal of prescribing opioids should be to maintain patient safety. A responsible prescriber should follow multiple steps to assure safe and effective care of their patient.

Steps a prescriber can take include (Manchikanti, Abdi, & Atluri, 2012):

1. Assessment and documentation of a comprehensive history including medical history, substance abuse, current medications (including opioids), psychiatric and psychosocial history.   
2. Establish a physical and psychological diagnosis and establish medical necessity before starting or maintaining opioid therapy. Those with mental illness are at higher risk to abuse medications.   
3. Screen for substance abuse history because substance abusers are at increased risk to misuse controlled substances.   
4. Establish goals in therapy in regard to pain control and functional goals.   
5. Use prescription monitoring programs to help determine patterns of prescription use and reduce abuse of medications. These are state-run databases that tract controlled substance prescriptions and help find issues with over prescribing and misuse patterns.   
6. Contraindications must be considered prior to prescribing opioids such as acute psychiatric instability, uncontrolled suicide risk, opioid allergy, respiratory instability, history or current abuse of substances or alcohol, currently using benzodiazepines, current use of heavy doses of other central nervous system depressants, medications currently being used that have severe drug interactions or those who practice diversion of controlled substances.   
7. Judiciously use imaging tests and other evaluations as some testing may increase fear, foster activity restriction, encourage maladaptive behaviors and encourage requests for more opioids.   
8. Provider and patient should have a written agreement (see Table 1) when opioids are used that reduce the risk of abuse, diversion, misuse and overuse.   
9. Discuss the risks and benefits of the medications.   
10. Get informed consent prior to prescribing controlled substances.   
11. Generally, opioid therapy should be started at low doses with short-acting medications.   
12. The use of long-acting opioids in high doses should be used only for severe intractable pain that cannot be adequately managed with short-acting opioids or moderate doses of long-acting opioids.   
13. Titration with long-acting opioids must be done with caution and overdose and misuse must be considered.   
14. Consider consultation for those who require high-dose opioid therapy.   
15. Ideally one provider should prescribe all opioids.   
16. Constipation must be monitored for and managed.   
17. Health care providers need to assure that they prescribe the lowest effective dose and the smallest quantity needed based on the expected length of the pain.   
18. Periodically review the treatment plan including any new information about the patient; their condition and their pain; and progress toward their goals.   
19. Keep accurate records.   
20. Be compliant with all laws and regulations related to controlled substances.   
21. Individualize treatment based on prior exposure to opioids, response to treatment and adverse events.   
22. Monitor for aberrant drug-related behaviors.   
23. Consider referral to psychology, psychiatry or addiction experts for those at high risk for or those who engage in aberrant drug-related behaviors.
24. Discontinue chronic opioid therapy in those who repeatedly engage in aberrant drug related behaviors, do not progress toward established goals, or those who experience significant side effects. Patients who have been taking the opioid for an extended time should have the medication tapered slowly. A ten percent taper per week will minimize the symptoms of withdrawal. Some recommend a faster taper such as 20-50 percent per week for those who are not addicted (Department of Veteran Affairs and Department of Defense, 2014).

While there are many opioids, morphine is considered by many as a standard comparator for other drugs. Morphine can be given orally, rectally, intravenously, subcutaneously or intramuscularly.

Morphine is used for moderate to severe acute pain and chronic serious pain. It comes in multiple formulations. For acute pain it is dosed at 10-30 mg every 4 hours for those who are opioid nave. It is available as tablet, solution, suppository and parenteral solution. The immediate release tablet is dosed 15-30 mg every 4 hours as needed and the oral solution is dosed 10-20 mg every 4 hours as needed. It can also be given rectally and is often dosed 10-20 mg every 4 hours as needed. Morphine also comes in a controlled release form, a sustained release form and an extended release form.

Longer acting formulations include:

Avinza: The initial dose for the opioid nave patient is typically 30 mg a day and 90 mg and 120 mg are only indicated for use in opioid-tolerant patents. When converting over from immediate-release morphine the first dose of Avinza may be taken with the last dose of IR formulation. The medication may be adjusted in 15-30 mg increments every 3-4 days. The maximum dose is 1600 mg a day because of the fumaric acid content.

Kadian: It is not indicated for initial opioid analgesia. For non-opioid tolerant patients, 30 mg once a day is recommended. Higher doses are indicted for opioid-tolerant patients. Titration may be done every 1- 2 days. When converting from other forms of morphine it may be given once or twice a day.

MS Contin is started at 15 mg every 8-12 hours with the dosage being adjusted every 1-2 days.

Side effects of morphine are similar to other opioid analgesics and include: dry mouth, constipation, bradycardia, hypotension, nausea, drowsiness, dizziness, mental status changes, fever, itching, weakness, hypoxia and urinary retention.

Morphine should not be used in those with a hypersensitivity to morphine, those with toxin mediated diarrheal disease, and those with severe/acute asthma, paralytic ileus or severe respiratory depression. The extended release form should not be used in those with GI obstruction.

The extended release forms of morphine are not interchangeable. Changing from one medication to another should be done only by those experienced in how to do this. Extreme caution should be used when using highly concentrated solution so over doses do not occur.

Drug interactions commonly seen with morphine include:

• Amphetamines may increase the effect of morphine   
• Anticholinergic agents may increase the side effects of morphine (constipation and urinary retention)   
• Antipsychotic agents with morphine may reduce blood pressure   
• Nasal azelastine (Astelin) with morphine enhances the central nervous system (CNS) depression effect   
• Clopidogrel therapeutic efficacy may be reduced with morphine   
• Diuretics side effects may be increased with morphine   
• Hydrocodone enhances CNS depression   
• Hydroxyzine enhances CNS depression   
• MAO Inhibitors enhances side effects of morphine   
• Selective serotonin reuptake inhibitors with morphine enhances the serotonergic effect and CNS depression   
• Zolpidem enhances the CNS depression

Morphine is pregnancy category C. It does enter breast milk and it is not recommended in those who are breast feeding.

Fentanyl can be given as an injection, transdermal patch (Duragesic), an oral transmucosal lozenge (Actiq), a sublingual tablet (Abstral), a sublingual spray (Subsys), a buccal tablet (Fentora), a buccal film (Onsolis) and a nasal spray (Lazanda). The transdermal patch is used in opioid tolerant patients with moderate to severe pain and is often started at 25 mcg per hour and changed every 72 hours.

Fentanyl can be used for multiple reasons including premedication for surgery, for general anesthesia, as an adjunct to general and regional anesthesia, and chronic pain management. The transdermal patch is indicated for around the clock pain management in those with chronic severe pain. Fentanyl transmucosal and intranasal is indicated for cancer pain.

While no official dosage adjustment is recommended in those with renal or hepatic impairment, those with mild to moderate renal or hepatic impairment should likely have the dose reduced by 50 percent with the patch and the use is not recommended in severe renal or hepatic impairment. Transmucosal and nasal spray has no specific recommendations for dose reduction in renal or hepatic impairment.

Common side effects of fentanyl include: edema, bradycardia, dehydration, respiratory depression, shortness of breath, diaphoresis, nausea/vomiting, constipation, dry mouth, application site erythema (patch), weakness, muscle rigidity, mental status changes, headache, sedation, and CNS depression.

As with most opioids contraindications includes: hypersensitivity, toxin mediated diarrheal disease, and paralytic ileus. It should not be used for short-term pain, post-operative pain and should not be used for those who have a severe respiratory disease. The transmucosal and nasal form of fentanyl is typically only used by specialists for opioid tolerant cancer patients.

The patch form should not be exposed to external heat as this may increase absorption of the medication. In addition, patients with a fever may also notice an increase in absorption of the medication. The patch should only be applied to intact skin and it contains aluminum and must be removed prior to an MRI.

Like many medications there are multiple potential interactions. Some more common interactions include:

• Alcohol may enhance CNS depression
• Beta-agonists may decrease the serum concentration of fentanyl
• Amphetamines may enhance the effects of fentanyl
• Anticholinergic medications along with fentanyl increase the risk of urinary retention and constipation
• Antipsychotic agents may increase the risk of low blood pressure
• Azelastine nasal spray may enhance CNS depression
• Beta-blockers with fentanyl enhance bradycardia
• Calcium channel blockers may enhance hypotension or bradycardia
• Hydrocodone may enhance CNS depression
• Selective serotonin reuptake inhibitors with fentanyl may enhance serotonergic properties
• Zolpidem effects may be enhanced

Fentanyl is pregnancy category C. It does enter the breast milk and is not recommended in the breast feeding mother.

Oxycodone is a schedule II controlled substance and is available in multiple forms.

• Immediate release (Roxicodone) is dosed 5-30 mg every 4-6 hours (lower range for opioid naive patients). There is also an abuse deterrent tablet (Oxceta) that comes as a 5 mg and 7.5 mg tablet.   
• The controlled release tablet (OxyContin) is indicated for those who require around the clock pain control. It is dosed 10 mg every 12 hours to start and titrated carefully. When changing from immediate release to extended release, start the extended release at half of the daily dose of oxycodone every 12 hours. When changing from transdermal fentanyl to extended release oxycodone, substitute 10 mg of extended release oxycodone every 12 hours for each 25 mcg/hour of fentanyl. The oxycodone should be started 18 hours after the removal of the transdermal fentanyl patch.   
• It also comes as an oral concentrate and oral solution.   
• Oxycodone is often combined with other analgesic agents such as acetaminophen (e.g., Percocet, Roxicet, Tylox), aspirin (e.g., Percodan, Endodan, Oxycodan) and ibuprofen (Combunox).

Those with a creatinine clearance less than 60 mL/min should have the dose adjusted down as serum concentration of oxycodone will increase in renal insufficiency. Those with hepatic impairment should have doses reduced; with the extended release formulation the starting dose should be lowered one-third to one-half and slowly titrated up to affect.

Side effects include: drowsiness, dizziness, itching, constipation, nausea and vomiting. Less common side effects include: dry mouth, headache, abnormal dreaming, blood pressure changes, diaphoresis, weakness and fever.

Oxycodone is contraindicated in those with paralytic ileus, significant respiratory depression, hypercarbia, acute or severe bronchial asthma, and GI obstruction.

Caution should be used in those with biliary tract impairment such as acute pancreatitis as it may lead to constriction of the sphincter of Oddi. It may lead to an elevation of intracranial pressure (ICP) and should be used carefully those with intracranial lesions, elevated ICP or a head injury.

Extended release tablets may be lodged into the GI tract including the throat in those with swallowing issues. It may also lad to intestinal obstruction or diverticulitis.

Common drug interactions with oxycodone:

• Alcohol may enhance CNS depression
• Amphetamines may increase the effect of oxycodone
• Anticholinergic agents may increase the side effects of oxycodone (constipation and urinary retention)
• Antipsychotic agents with oxycodone may reduce blood pressure
• Nasal azelastine (Astelin) enhances CNS depression
• Diuretics side effects may be increased with oxycodone
• Hydrocodone enhances CNS depression
• Hydroxyzine enhances CNS depression
• MAO inhibitors enhances side effects of oxycodone
• Mirtazapine may enhance CNS depression
• Rifampin may decrease the serum concentration of oxycodone
• Selective serotonin reuptake inhibitors with oxycodone enhances the serotonergic effect and CNS depression
• Zolpidem enhances the CNS depression

Oxycodone is pregnancy category B and D if used for an extended period of time or near term. It does enter breast milk and is not recommended in those who are breast feeding.

Hydrocodone, which was classified as a Schedule II Controlled Substance in October of 2014, is available as a combination pill with non-narcotic analgesia (e.g., Lorcet, Lortab, Norco and Vicodin) and by its self in an extended release form. The combination pill has a short acting version of hydrocodone and is dosed 2.5 to 10 mg of hydrocodone every 4-6 hours as needed for moderate to severe pain.

Hydrocodone extended release (Zohydro ER) is typically dosed 10 mg every 12 hours in treatment naive patients. It is used for severe pain requiring around the clock dosing of hydrocodone. The dose may be increased every 3-7 days in 10 mg increments.

Those with severe hepatic impairment should start at the lowest dose and titrate up very slowly while monitoring for side effects. Caution should be used with renal impairment as plasma concentration may rise.

Side effects include: constipation, nausea, vomiting, dry mouth, drowsiness, headache, dizziness, pruritus and nausea.

Contraindications to hydrocodone include: paralytic ileus, severe asthma, severe respiratory depression and hypercarbia.

Drug interactions

• Alcohol may enhance CNS depression
• Amphetamines may increase the effect of hydrocodone
• Anticholinergic agents may increase the side effects of hydrocodone (constipation and urinary retention)
• Nasal azelastine (Astelin) enhance the CNS depression
• Diuretics side effects may be increased with hydrocodone
• MAO inhibitors enhances side effects of hydrocodone
• Selective serotonin reuptake inhibitors with hydrocodone enhances the serotonergic effect and CNS depression
• Zolpidem enhances the CNS depression?

This is pregnancy category C. The extended release form minimally enters the breast milk and should be used with caution in breastfeeding and the combination pill has been shown to enter breast milk and its use is not recommended.

As of August 18, 2014 the DEA placed tramadol into a Schedule IV of the Controlled Substance Act. It is indicated for moderate-to-severe pain and the immediate release form is dosed at 50-100 mg every 4-6 hours for a maximum of 400 mg a day.

Tramadol is also indicated for chronic moderate-to-severe pain. For those who do not need a rapid onset of pain relief and/or affected by side effects, it may be dosed at 25 mg/day and titrated up every 3 days to 50-100 mg every 4-6 hours to a maximum of 400 mg a day.

Tramadol also comes in an extended release form, ConZip and Ultram ER, which is dosed 100 mg once a day and may be titrated by 100 mg every five days to a maximum dose of 300 mg a day.

When prescribing tramadol to older adults use the lower end of the dosage range and titrate slowly. In those over 75 years old, 300 mg a day should not be exceeded and utilize extreme caution with the extended release form.

In those with a creatinine clearance less than 30 mL/min, only the immediate release formulation should be used with doses of 25-100 mg split every 12 hours (maximum dose of 200 mg a day). In those with severe liver impairment, the immediate release form should be given at a maximum of 50 mg every 12 hours.

Side effects include: flushing, dizziness, constipation, nausea, vomiting, dyspepsia, itching, headache, somnolence, insomnia and weakness. Less common side effects include: orthostatic hypotension, mental status changes, euphoria, rash, hot flashes, diarrhea, dry mouth, anorexia, joint pain, blurred vision and sweating.

Patients may experience withdrawal symptoms from tramadol that may include nausea, diarrhea, anxiety, pain, sweating, tremor and rigors. Extended use of tramadol may lead to dependence and these medications should be tapered slowly to reduce the risk of withdrawal symptoms.

Tramadol is contraindicated in those who are hypersensitive to the agent and those with severe liver or kidney impairment. The extended release tablet should not be used with psychotropic drugs, opioids, hypnotics, acute intoxication with alcohol or centrally acting analgesics and the extended release capsule formulation should not be used in those with severe respiratory depression, severe asthma or hypercapnia.

Tramadol has been shown to increase the risk of seizures. This risk is increased in those who take serotonin reuptake inhibitors, tricyclic antidepressants, neuroleptics, other opioids, or other drugs that lower the seizure threshold. Risk may also be increased in those who have seizures or are at risk for seizures such as those who have a CNS infection, cancer, history of head trauma or while patients are going through drug or alcohol withdrawal.

Caution should be used in those with respiratory disease as those with significant disease may be at increased risk for respiratory depression.

Drug interactions

• Alcohol may enhance CNS depression
• Amphetamines may increase the effect of tramadol
• Anticholinergic agents may increase the side effects of tramadol (constipation and urinary retention)
• Antiemetics may reduce the effects of tramadol
• Antipsychotics and tramadol may result in reduced blood pressure, increased risk of neuroleptic malignant syndrome and increased risk of serotonin syndrome
• Nasal azelastine (Astelin) enhances CNS depression
• Carbamazepine with tramadol may enhance CNS depression; tramadol may reduce the therapeutic effect of carbamazepine
• Cyclobenzaprine and tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
• Diuretics side effects may be enhanced with tramadol
• Hydrocodone may enhance CNS depression
• Hydroxyzine may enhance CNS depression
• MAO inhibitors with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
• Metoclopramide with tramadol may increase side effects of metoclopramide or increase the risk of serotonin syndrome or neuroleptic malignant syndrome
• Selective serotonin reuptake inhibitors with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
• Tricyclic antidepressants with tramadol may increase the risk of seizures or increase the risk of serotonin syndrome
• Zolpidem enhances CNS depression

Tramadol is pregnancy category C. It enters the breast milk and is not recommended in lactating women.

Oxymorphone, a schedule II medication, can be given intravenously, subcutaneously, intramuscularly or orally. For acute pain the immediate-release tablet (Opana) is used at 5-20 mg every 4-6 hours as needed for opioid nave patients. For those with chronic severe pain the extended release tablet is used (Opana ER) and is started at 5 mg every 12 hours and may be titrated up at 5-10 mg increments every 12 hours every three to seven days. Caution should be used in those with a creatinine clearance less than 50 mL/minute and the medication should not be used in moderate to severe hepatic impairment. Oxymorphone is pregnancy category C and it is unclear if it is excreted in breast milk and should therefore be used cautiously.

Hydromorphone can be given orally, rectally, subcutaneously, intramuscularly or intravenously. The oral medication comes in standard and extended release forms. The standard form is used for moderate to severe pain and is often dosed 2 to 4 mg every 4-6 hours. The oral liquid is typically dosed 2.5 to 10 mg every 3 to 6 hours. Parental and oral doses are not equivalent. The parenteral dose is five times more potent than the oral dose. The long acting form (Exalgo) is used for opioid tolerant patients who have chronic severe pain. It is dosed 8-64 mg once a day. Hydromorphone is pregnancy category C and is excreted in breast milk. It is not recommended for lactating women.

Methadone can be given intravenously, subcutaneously, intramuscularly or orally. The oral dose is started in the opioid nave patient at 2.5 every 8-12 hours. Methadone is a high risk drug to lead to overdose. It has a half-life of up to five days and may accumulate in the body. Methadone may also prolong the QT interval leading to cardiac arrhythmias especially at doses higher than 120 mg a day. Methadone should be used for severe pain that has not been responsive to other agents and only by clinicians with specific training in the use of methadone. Methadone is also used in detoxification.

Tapentadol (Nucynta, Nucynta ER) is used for acute moderate to severe pain and started at 50-100 mg every six hours for the immediate-release formulation. The starting dose for the extended-release tablet is 50 mg every 12 hours. For chronic pain it is typically dosed 50-250 mg two times a day as needed. The maximum dose is 500 mg a day. This medication is not recommended for those with severe liver or renal insufficiency. It is also indicated for diabetic peripheral neuropathy.

Propoxyphene has been taken off the US market as it has been linked with fatal cardiac arrhythmias. Meperidine is not recommended as a first line agent for chronic pain as it is associated with high rates of central nervous system toxicity.

Alprazolam (Xanax) is indicated for anxiety and panic disorder. Approved in 1981, the immediate-release form is available as a 0.25 mg, 0.5 mg, 1 mg and 2 mg tablet. It is also available as an oral disintegrating tablet and oral solution. For anxiety it is dosed 0.25 to 0.5 mg every 6-8 hours with titration every 3-4 days. It is also available as an extended release form as alprazolam XR (Xanax XR) which is available as 0.5 mg, 1 mg, 2 mg, and 3 mg. It is started at 0.5 to 1 mg once a day and increased every 3-4 days to effect. Caution is recommended in those with renal impairment and advanced hepatic impairment. It is pregnancy category D and is excreted in the breast milk.

Diazepam (Valium) is available as a 2 mg, 5 mg and 10 mg tablet and as an oral solution, rectal gel and injectable solution. It is dosed for anxiety at 2-10 mg every 6-12 hours orally. It has a long half-life and can lead to problems as it accumulates and may lead to increased side effects when dosed chronically. In addition to anxiety, diazepam can also be used for alcohol withdrawal, sedation, muscle spasm or seizures. It is pregnancy category D and is excreted in the breast milk.

Chlordiazepoxide (Librium) is indicated for anxiety and is available as a 5 mg, a 10 mg, and a 25 mg capsule and is often dosed 5-10 mg every 6-8 hours for mild to moderate anxiety and 20-25 mg every 6-8 hours for severe anxiety. It is also used commonly for alcohol withdrawal. Dose adjustment is not necessary in renal impairment until the creatinine clearance is less than 10 mL/min. It is pregnancy category D and is excreted in the breast milk.

Clonazepam (Klonopin) is indicated for panic disorder and seizure disorder. Approved in 1975, it is available as a tablet in a 0.125 mg, 0.25 mg, 0.5 mg, 1mg and 2 mg tablet. For anxiety it is dosed 0.25 mg every 12 hours to start and may be titrated up after three days. It is pregnancy category D and is excreted in the breast milk.

Lorazepam is available as a tablet, oral concentrate and injectable solution. It is available as a 0.5 mg, 1 mg and 2 mg tablet. For anxiety disorders it is given 2-3 mg every 8-12 hours as needed to a maximum of 10 mg a day. It can also be used for sedation, status epileptics and short-term insomnia. No dosage adjustment is necessary in renal impairment with the oral formulation. Those with severe hepatic impairment require caution when using lorazepam. It is pregnancy category D and is excreted in the breast milk.

Lorazepam, along with oxazepam (Serax) and temazepam (Restoril), are safer benzodiazepines for those with cirrhosis, multiple medical issues, on multiple medications or are older as they are metabolized in the liver through glucuronidation.

John is 38 year-old male with chronic back pain due to three herniated discs and spinal stenosis which was first diagnosed after a motor vehicle accident three years ago. He currently rates the severity of his back pain as a 9/10 and has been unable to work as a plumber due to his pain. The pain is described as dull and constant with occasional sharp exacerbation in the low back with the pain increasing with bending, prolonged standing and walking. The patient denies any loss or change of bowel/bladder control, history of IV drug use, recent infection, progressive neurological complaints, night pain, night sweats, weight loss or fever. The pain occasionally radiates into the right buttock. The patient is able to do all of his ADLs, but does report poor sleep at night.

He has a past medical history of hypertension and recently has developed stage II chronic kidney disease thought to be secondary to hypertension and excessive use of ibuprofen. His only current medication is lisinopril to control his blood pressure.

He has had multiple treatment modalities including four rounds of physical therapy, chiropractic treatment and multiple medications. He tried to control his back pain on acetaminophen, naproxen, ibuprofen, the lidocaine patch and topical NSAIDs without relieve. The patient experienced significant tremor and an increase in blood pressure while on tramadol. A series of epidural injections did not help. Surgery was discussed, but the patient refused this option.

John is married and has one daughter who lives over 500 miles away with her biological mother. He has limited financial means and lives pay check to pay check. He has a prior history of alcohol abuse, but has not had a drink in five years. He is currently a smoker. He denies any history of substance abuse and there is no family history of alcohol or substance abuse.

Physical exam showed a patient with a slow deliberate gait, a limited range of motion in the spine with no obvious deformity, swelling or erythema. There is mild tenderness on the right side of the spine from the area of L4 to S1 as well as tenderness in the right sacroiliac joint. Normal reflexes, normal sensation, normal strength and no atrophy is noted in the lower extremities. The straight leg raise test is normal.

An MRI was done one year ago that was significant a herniated disc at the L5/S1 level and mild spinal stenosis.

The Opioid Risk Tool was administered and it was determined that the patient is at moderate risk for opioid abuse. He signs a written opioid treatment agreement that outlines the conditions of the opioid therapy. His past medical records were verified suggesting he is not lying.

The patient is prescribed hydrocodone/acetaminophen 5 mg/500 mg, two tablets every six hours as needed (56 tablets) for 1 week.

Five days later he calls for an early refill and reports that the medication is really not helping his pain and he just lies around all day.

He comes back into the office for a re-evaluation. He reports he needed to take more pain medication than prescribed. His wife confirms that he has been lying around all day and she believes it is because he is having so much pain. It was reviewed with the patient that he violated the opioid agreement. A urine sample was obtained that showed no illicit substances or medications that would not be expected in the urine.

While the patient is at moderate risk to abuse medication, his past medical history was all confirmed. He was referred to a psychiatrist and a pain specialist. He was agreeable to both. He was able to get into the psychiatrist within one week, but the pain specialist appointment was four weeks out. The patient saw the psychiatrist and he diagnosed the patient with depression and started him on a sertraline. The psychiatrist was unable to make an assessment related to opioid abuse.

With the help of the pain specialist, oxymorphone ER 5 mg was ordered every 12 hours. The patient was told to follow up in one week to assess effectiveness. After one week the patient reports he is more functional but still in a lot of pain. The dose of oxymorphone ER was increased to 10 mg every 12 hours. After one more week he was given oxymorphone IR 5 mg to be used one hour before exercise. This allowed the patient to not only function well, but begin participating in an exercise program. The patient was ordered a bowel stimulant (Senna) with a stool softener (Colace) to prevent constipation.

The patient is prescribed fourteen pills oxymorphone ER 10 mg (to be taken twice a day) and seven pills of oxymorphone IR 5 mg (to be taken once a day before exercise) once a week. Part of the agreement was that they are to be given by the patient's wife to reduce the risk of misuse.

Ms. L is a 52 year old female with a history of bilateral knee pain; she currently rates the pain as an 8/10 in her right knee and 5/10 in her left knee. She takes meloxicam 7.5 mg twice a day and uses 1000 mg of acetaminophen for breakthrough pain about 3 times a day. She has been using this regime for the past 6 months, but over the last month she has not been getting adequate relief from her pain and has been progressively disabled and has stopped exercising.

The pain is attributed to osteoarthritis and has been progressively worsening over the last 1-2 years. She has a past medical history of hypertension, dyslipidemia, depression, obesity and osteoarthritis. She has a past-surgical history of a hysterectomy approximately five years ago. She is currently on simvastatin, lisinopril, meloxicam, acetaminophen and aspirin. She has no known allergies.

She has no history of alcohol, drug or substance abuse. She has a strong family network including a supportive husband of 25 years and 2 sons who live within twenty miles of her home. She has a past history of depression, but is currently not depressed.

The physical exam is significant for obesity (BMI of 34). She has crepitus to both of her knees and is unable to fully extend the right knee due to pain.

An x-ray demonstrates moderate arthritic changes in both knees. The patient is unwilling to consider surgery of her knees.

The prescriber offers tramadol immediate release 25 mg in the morning, which is titrated every three days in 25 mg increments as distinct doses to 100 mg/day (25 mg four times a day). Pain control was still not adequate and the dose was then increased by 25 mg every three days to 50 mg every 6 hours.

Pain control was significantly improved and then the patient was give tramadol SR 200 mg once a day. The patient was able to function and exercise. Her quality of life was much improved.

Controlled substances are a common weapon used by prescribers to manage a variety of conditions including pain, anxiety, attention deficit disorder and others. Proper use of these medications is critical because there is significant risk including addiction, misuse, constipation, falls and even death with these agents. Prescribers need to be well versed in their use.

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