Is Your OTC Pain Reliever Going to Kill You?

Although acetaminophen (Tylenol) is heavily marketed for its safety, FDA recommends health care professionals to discontinue prescribing and dispensing drug products with more than 325 mg of acetaminophen due to the high risk of liver injury.  Severe liver injury may occur in patients who:

  • Took more than the prescribed dose of an acetaminophen containing product in a 24 hour period.
  • Took more than one acetaminophen containing product at the same time.
  • Drank alcohol while taking acetaminophen products.

Acetaminophen is widely used as an over the counter pain reliever and fever medication and is often combined with other ingredients such as cough and cold ingredients.  Patients may be unaware that many products (both prescription and OTC) may contain acetaminophen, making it easy to accidentally take too much [1-5]. In fact,  acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain[16].

Ibuprofen (Motrin, Advil) is also widely used for pain and inflammation but not without risk.  Ibuprofen carries a black box warning from the FDA regarding the cardiovascular and gastrointestinal risks associated with its use.  Patients taking ibuprofen have an increased risk of serious cardiovascular thrombotic events including myocardial infarction and stroke. Researchers in Denmark observed a nearly threefold increase in the number of deaths from gastrointestinal bleeding within one year of ibuprofen prescription [14].  The risk of side effects is so high for elderly patients the American Geriatrics Society has recommended that patients over the age of 65 avoid NSAID use if at all possible [6-10].  This real risk was studied by RE Tarone who noted a marked rise in baseline rate of gastrointestinal bleed with advancing age with the large majority of cases occurring among persons age 65 or older.  The average relative increase in risk of gastrointestinal bleeding was found to be fourfold or slightly higher in NSAID users and six fold or higher at heavy prescription levels [15].

NSAID High Risk Groups

Medications such as Tylenol and ibuprofen, which are readily available over-the-counter, are perceived to be safe medications; but research has proven that they are not without risk.  Physicians, payers and patients are requesting a safe more effective alternative to treat pain which becomes increasingly important as the population ages.

Medical foods such as Theramine treat the dietary deficiencies that are associated with pain and inflammation.  Pain reduction is accomplished by moderating responsiveness to noxious stimuli, regulating the transmission of pain signals and controlling inflammation. The use of medical foods has been long standing and there have been no reports of GI bleed in over 10 years on the market.

Two multi-center double-blind clinical trials established the safety and efficacy of Theramine in the treatment of chronic back pain.  In a clinical study comparing the medical food Theramine and a non-steroidal anti-inflammatory medication, Theramine was shown to be more effective than low dose NSAIDs in treating low back pain.  Clinical data indicate significant reduction in back pain with the administration of Theramine alone, while administration of a low dose NSAID had no appreciable effect on pain.

An important observation by researchers EL Fosbol and L Kober note that, “Individual NSAIDs have different cardiovascular safety that needs to be considered when choosing appropriate treatment.  In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals.  This notion is also valid for healthy individuals and underlines the importance of critical use of NSAID therapy in the general population and also that over-the-counter retail of NSAIDs should be reassessed.”[13]

 

REFERENCES

 

1.  Wolf M; King J; Jacobson K; et al “Risk of Unintentional Overdose with Non-prescription Acetaminophen Products”  J Gen Intern Med 2012 Dec; 27(12): 1587-1593

2.  “Acetaminophen Toxicity in Children” Pediatrics vol. 108 No. 4 Oct. 1 2001

3.  Farrell S; Tarabar A; et al “Acetaminophen Toxicity” Medscape June 24, 2011

4.  Plaisance K “Toxicities of Drugs Used in the Management of Fever” Clinical Infectious Diseases 2000 31 Supp 5: S219-S223

5.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm381650.htm

6.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085282.htm

7.  Pilotto A; Franceschi M; Leandro G; Di Mario F; “NSAID and aspirin use by the elderly in general practice:  effect on gastrointestinal symptoms and therapies:  Drugs Aging 2003; 20(9): 701-10.

8.  Smith SG “Dangers of Non-steroidal Anti-inflammatory drugs in the elderly” Can Fam Physician vol. 35 March 1989

9.  American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults

10.  Gurwitz JH; Everitt DE; Monane M; Glynn RJ, Choodnovskiy I; Beaudet MP; Avorn J; “The impact of ibuprofen on the efficacy of antihypertensive treatment with  hydrochlorothiazide in elderly persons” J Gerontol A Biol Sci Med Sci 1996 Mar; 51 (2): M74-9

11.  Shell WE; Charuvastra E; DeWood M; May L; Bullias D; Silver D “ A Double-blind controlled trial of a single dose naproxen and an amino acid medical food Theramine for the treatment of low back pain”  Am J of Ther 2010

12.  Shell WE; Pavlik S; Roth B; Silver M; Breitstein M; May L; Silver D “ Reduction in pain and inflammation associated with chronic low back pain with the use of the medical food Theramine”  Amer J of Ther 2014

13.  Fosbol EL; Kober L; Torp-Pedersen C; Gialason GH “ Cardiovascular safety of non-steroidal anti-inflammatory drugs among healthy individuals”  Expert Opin Drug Saf 2010 Nov; 9(6): 893-903

14.  Lipworth L; Friis S; Blot Wj; McLaughlin JK; Mellemkjaer L; Johnsen SP; Norgaard B Olsen JH “ A population based cohort study of mortality among users of ibuprofen in Denmark”  Am J Ther 2004 May-Jun; 11(3): 156-63

15.  Tarone RE; Blot WJ; McLaughlin JK “Nonselective non-aspirin non-steroidal anti-inflammatory drugs and gastrointestinal bleeding:  relative and absolute risk estimates from recent epidemiologic studies”  Am J Ther 2004 Jan-Feb; 11(1): 17-25

Safer Options for Pain Management

Pain is complex and there are several treatment options to choose from depending on the type of pain you are experiencing including medications, therapies and mind-body techniques.  The most common treatment consists of analgesics:  narcotic (opioid) and non-narcotic (non-opioid) analgesics.

Narcotics vs NSAIDS
Primary Differences Between Narcotics and NSAIDs

Narcotic analgesics are derived from or related to opium.  Opioids bind to opioid receptors which are present in many regions of the nervous system and are involved in pain signaling and control.  Opioid analgesics relieve pain by acting directly on the central nervous system.  They block incoming pain signals but also work in other parts of the brain, modulating pain receptors in the nervous system, primarily located in the brain and the spinal cord.

Non-opioid analgesics or NSAIDs work by blocking the production of prostaglandins by inhibiting the cyclooxygenase enzyme and therefore decreasing the formation of pain mediators in the peripheral nervous system.   Non-opioids work more directly on injured or inflamed body tissue. In a basic sense, opioids decrease the brain’s awareness of the pain whereas the non-opioids affect some of the chemical changes that normally take place wherever body tissues are injured or inflamed.

Although non-opioids are often preferred for certain types of chronic pain, they have two serious drawbacks.  The first is the ceiling effect; Non-opioids have an upper limit of pain relief that can be achieved.  Once the upper limit is achieved; increasing the dosage will not provide any further pain relief but may exacerbate side effects.  Opioids on the other hand tend not to have a ceiling.  The more you take, the more pain relief you will get.  The second major drawback of non-opioids is the side effects profile.  The side effects of NSAIDS make it impossible for certain patient populations to use NSAIDs such as those with history of peptic ulcer disease, cardiovascular disease and the elderly. In 2014, the American Academy of Neurology determined that the risks of opioids outweigh the benefits for certain chronic pain conditions.

Treatment of pain with the use of medical foods gives patients a safer option for pain management by approaching pain from a new perspective.  Medical foods treat the nutritional deficiencies that are found in patients with acute and chronic pain.  By restoring an optimal balance between the chemicals in the body, substances called neurotransmitters, that are responsible for transmitting and dampening pain signals, one can better manage pain.

Research has found low levels of the amino acids gluatamate, tryptophan, arginine, serine, and histidine in patients with chronic and acute pain.  The perception of pain can be modified by providing amino acids and nutrient precursors to the key neurotransmitters involved in the pain process. Amino acids are able to cross the blood brain barrier and are necessary to produce the appropriate neurotransmitters needed to reduce pain signals and lower inflammation. Increasing the intake of amino acids and nutrients lead to an increase in neurotransmitter levels [1].

The theory that the body’s need for amino acids and nutrients are modified by a disease has been long recognized and is supported by studies that reflect changes in plasma, urinary and tissue levels of nutrients with modified intakes of these nutrients [2].   There are various reasons for depletion of nutrient levels including diet, metabolic demands and genetics.  The required amount for each patient varies depending on the duration and severity of pain. Addressing the increased demand for amino acids and nutrients is a key component for improving clinical outcomes.

Two double-blind clinical trials compared Theramine, a medical food specially designed to address the increased amino acid and nutrient requirements of pain syndromes, to low dose naproxen and ibuprofen.  In both studies, Theramine showed statistically greater pain relief than either naproxen or ibuprofen.  This was measured by patient report and a reduction in the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) [3, 4].  Treatment with amino acid precursors was associated with substantial improvement in chronic back pain and a reduction in inflammation.

Pain Reduction with TheramineThe improvement in pain directly correlated with increased amino acid precursors to neurotransmitters in the blood.

Theramine is designed using Targeted Cellular Technology (TCT), which facilitates the uptake and utilization of the neurotransmitters precursors that are used in the modulation of pain.  TCT allows for the production of neurotransmitters from ingestion of smaller amounts of amino acids to elicit the same response as larger amounts, making daily dosing more feasible and reducing the potential for tolerance.

At least 100 million adult Americans suffers from chronic pain, a safe and effective treatment option such as medical foods that do not treat symptoms alone but addresses the distinctive nutritional needs of adults who have different or altered physiologic requirements due to pain is vitally needed.

To date, Theramine has been in clinical use for over 10 years with no report of GI bleed or adverse side effects and the clinical trials of Theramine clearly support the theory that the nutritional management of pain syndromes is a safe and effective treatment for pain.

The Dangers of NSAIDs

The most commonly prescribed drugs for pain are Non-Steroidal Anti-Inflammatory drugs (NSAIDs).  Approximately 98 million prescriptions for NSAIDs were filled in the United States in 2012 [IMS 2012] and this number does not include NSAIDs that are purchased over the counter.  Although effective in treating pain and inflammation, NSAIDs are linked to adverse side effects which make them inappropriate for use in many patient populations.  There are several serious side effects and toxicity related to use of traditional NSAIDs. Toxic side effects of traditional NSAIDs include:

  • Stomach ulceration and/or bleeding
  • Kidney damage
  • Easy bruising because of loss of platelet function
  • Exacerbation of cardiovascular conditions

Recent studies have also highlighted a higher risk of atrial fibrillation with NSAID use [1] and an increase risk of bleeding and events such as heart attack, stroke or cardiovascular death with the use of NSAIDs in conjunction with antithrombotic therapy [2].

NSAIDs work to reduce pain and inflammation by inhibiting cyclooxygenase, an enzyme.  The action of inhibiting cyclooxygenases, reduces pain and inflammation but is also responsible for many of the side effects of NSAIDs.  This inhibition is problematic because it also inhibits some important functions such as the repair and maintenance of the stomach lining.  This is why stomach ulceration and irritation is so common with the use of NSAIDs.

Inhibition of cyclooxygenase is also associated with reductions in prostaglandin synthesis and is associated with less sodium being excreted in urine and constriction of blood vessels.  This effect of NSAIDs on blood pressure may increase mean arterial pressure by as much as 5 to 6 mm Hg in hypertensive patients.   This consequence may be of particular relevance in patients with preexisting hypertension, edema or congestive heart failure.

One study noted the rate of new-onset hypertension developing in elderly patients for whom nonselective NSAIDs were prescribed was 27% [3]

The extremely high risk of side effects with such commonly used medication resulted in a quest for an analgesic/anti-inflammatory that could provide therapeutic efficacy equivalent to that of traditional NSAIDs but without the gastrotoxicity.

The use of medical foods to treat the dietary deficiencies associated with pain and inflammation has proven to be a safe and effective method for pain control.  Two double-blind, randomized,  trials, which compared Theramine to low dose naproxen and ibuprofen demonstrated statistically significantly reduction in inflammation as measured by inflammatory markers, CRP and IL-6 as well as improvement in low back pain.  Theramine was shown to be an effective pain medication but also an effective anti-inflammatory agent without the risk of gastrointestinal bleeding or other serious side effects.

All of the ingredients in Theramine are GRAS (generally recognized as safe) products and carries no risk of addiction or attenuation.  Theramine has been on the market for 10 years without report of GI bleed or serious adverse side effects.

There are several patient populations that should avoid NSAIDs due to the high risk of side effects.

  • Patients over 65 years of age
  • Previous GI history such as peptic ulcers or previous GI bleed
  • Patients with cardiovascular disease
  • Patients with liver disease
  • Patients with kidney disease
  • Patients on anti-coagulants or low dose aspirin

The cumulative evidence of the danger of NSAIDs is an important reminder that the while NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications, particularly among high risk patients must be carefully considered.

 

1.  Gang Liu, MD, PhD, Yu-Peng Yan, MD, Xin-Xin Zheng, MD, Phd, Yan-Lu Xu, MD, Phd, Jie Lu, MD, Ru-Tai Hui, MD, Phd, Xiao-Hong Huang, MD, Phd “Meta-Analysis of Nonsteroidal Anti-Inflammatory Drug Use and Risk of Atrial Fibrillation” The American Journal of Cardiology Nov. 15, 2014 Vol. 114, Iss. 10

2. Anne-Marie Schjerning Olsen, Gunnar H. Gislason, Patricia McGettigan, Emil Fosbøl, Rikke Sørensen, Morten Lock Hansen, Lars Køber, Christian Torp-Pedersen, Morten Lamberts. Association of NSAID Use With Risk of Bleeding and Cardiovascular Events in Patients Receiving Antithrombotic Therapy After Myocardial Infarction. JAMA, 2015; 313 (8): 805

3.  Solomon DH, Schneeweiss S, Levin R, Avorn J. “Relationship between COX-2 specific inhibitors and hypertension” Hypertension. 2004; 44: 140–145

Pain Management without Harmful Side Effects

The reduction and management of pain can involve many approaches: prescription medicines, over the counter medicines, medical foods, cognitive behavioral therapy, physical exercise, surgery, nutritional modification, pain education, massage, biofeedback, music, guided imagery, laughter, distraction, acupuncture, and nerve stimulation.  Two or more approaches combined can have a synergistic or additive effect that is greater than the sum of the parts.  One approach, medical foods, has medicinal value that is just beginning to be understood and can be used as a stand-alone therapy or adjacent treatment for chronic pain.

Due to its’ additive effect and low side-effect profile, Theramine®, a medical foods, can be used with high-risk patients over the age of 65 as an alternative to NSAIDs or narcotics.  Adding Theramine to a pain treatment protocol can lead to a reduction in previously prescribed narcotics and minimize the use of NSAIDs or both.  The ingredients in Theramine are Generally Recognized As Safe (GRAS) by the FDA, have no risk of addiction or adverse GI or cardiovascular side effects.  Reducing the burden of adverse side effects while improving clinical outcomes is critical for the overall patient care and a return to activities of daily living.

Two studies comparing Theramine to a low dose NSAIDs in adults 18 years of age and above found Theramine to be more effective than either naproxen or ibuprofen alone for inflammatory pain.  When Theramine was given in combination with the low dose of either product the results were even more beneficial.  Incorporating the use of Theramine into a clinical pain management protocol, allows physicians the flexibility to use less of a narcotic or NSAID pain reliever and potentially eliminate their use all together.

The two studies comparing the medical food Theramine and a non-steroidal anti-inflammatory medication, Theramine was shown to be more effective than low dose NSAIDs in treating low back pain.  Clinical data indicates significant reduction in back pain with the administration of Theramine alone, and as an adjunct therapy to a low dose NSAID, while administration of a low dose NSAID had no appreciable effect on pain. The use of Theramine as either a standalone or adjunct therapy can significantly improve pain perception.

Theramine is encapsulated with a patented technology that promotes the rapid cellular uptake and conversion of milligram amounts of amino acids and nutrients into the specific neurotransmitters responsible for modulating pain and inflammation.  This patented technology allows Theramine to be effective without losing efficacy over time.

Two multicenter double blind trials have established the safety and efficacy of Theramine in the treatment of chronic back pain. Pain fell by 63% with administration of Theramine and an NSAID as measured by the Roland- Morris Index (Figure 1), and by 62% as measured by The Oswestry Disability Index.

Pain Scale Graph

Traditional pain medication will always have its place in therapeutic treatment and, if used properly, is very effective.  However, physicians, insurance companies, employers and patients are requesting safer, more effective alternatives to treat pain without harmful and costly side effects. The rapidly increasing population of patients 65 years of age and older is a major concern for both physicians and insurance companies as the pain-related costs to overall U.S. health care expenses are likely to rise proportionally as well. The economic impact of pain is certain, as are the physical, emotional, and social impact for millions of people. Reducing the burden of treating chronic pain is a societal necessity, a medical challenge, and an economic requirement.

#medicalfoods #NSAIDs #theramine

Opioid Receptors Impaired in Fibromyalgia Patients

µ-Opioid Receptors Impaired in Fibromyalgia Patients

Chronic idiopathic pain associated with fibromyalgia is complex to manage and is often associated with other co-morbidities such as depression. A recently published University of Michigan study looked closely at µ-opioid receptor availability in fibromyalgia patients, providing sound physiologic data confirming the widespread consensus that the inability of these patients to process pain signals effectively is largely due to the inability of receptors in key areas of the central nervous system to bind to analgesic opioids.

The clinical management of fibromyalgia is very complex and requires a multi-modal approach to pain management that is specific to the individual patient.  Narcotic pain medications are largely ineffective at mitigating idiopathic pain in fibromyalgia patients and often lead to many more serious side-effects that can exacerbate and prolong the condition. The widespread use of narcotics to manage non-malignant chronic pain is a serious problem in the United States and there is no medical evidence showing that these drugs actually work to treat the chronic pain of fibromyalgia. The study’s results are further evidence for clinicians that the use of non-narcotic interventions for pain management of fibromyalgia are more effective treatment options.

Medical foods are a good example of a therapeutic alternative for the treatment of fibromyalgia.  These prescription-only medications treat the nutritional deficiencies in chronic disease and not just the symptoms.  Patients diagnosed with fibromyalgia, for example, may have an increased need for precursors of the neurotransmitters nitric oxide, GABA (gamma-amino butyric acid), serotonin, and acetylcholine.  These include amino acids and nutrients such as arginine, glutamate, tryptophan, acetyl-L-carnitine, and choline. The clinical dietary management of fibromyalgia contains the specific elements the body requires to stimulate production of the neurotransmitters required to support effective pain control.

As a practicing board-certified rheumatologist and internist, I have prescribed medical foods to patients for the treatment of fibromyalgia for a number of years.  Healthcare providers and patients interested in a more efficacious treatment for fibromyalgia with little or no side effects should familiarize themselves with the class of medications regulated by the FDA as medical foods.