All You Need To Know About HIV And Pain

Well not quite all and despite this being an earlier article, updated in June 2012,  they still don't issue any information about the fact that Lyrica (Pregabalin) has been withdrawn for HIV-related pain by the company that makes it. However, for the rest, this comprehensive article from aidsetc.org (see link below) is about as good an overview as you can find. As they say, 30% to 60% of HIV patients experience some degree of pain related to their condition, so well-explained articles like this are essential for people trying to put two and two together and not come up with five. If, for instance, you've just realised that your neuropathic symptoms are not just a temporary irritation, you may be looking for information that gives a solid framework to what you're feeling - this article will help you make sense of what's happening.

Pain Syndrome and Peripheral Neuropathy

Guide for HIV/AIDS Clinical Care, HRSA HIV/AIDS Bureau

June 2012

Background

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." Pain is subjective, it is whatever the patient says it is, and it exists whenever the patient says it does. Pain is a common symptom in people with HIV infection, especially those with advanced disease. It occurs in 30-60% of HIV/AIDS patients and can diminish their quality of life significantly. Like cancer patients, HIV patients experience an average of 2.5 to 3 types of pain at once. Pain in HIV-infected patients may have many causes (as discussed below).

Peripheral Neuropathy

Pain from HIV-associated peripheral neuropathy is particularly common, and may be debilitating. Peripheral neuropathy is clinically present in approximately 30% of HIV-infected individuals and typically presents as distal sensory polyneuropathy (DSP). It may be related to HIV itself (especially at CD4 counts of <200 cells/µL), to medication toxicity (e.g., from certain nucleoside analogues such as stavudine or didanosine), or to the effects of chronic illnesses (e.g., diabetes mellitus). Patients with peripheral neuropathy may complain of numbness or burning, a pins-and-needles sensation, shooting or lancinating pain, and a sensation that their shoes are too tight or their feet are swollen. These symptoms typically begin in the feet and progress upward; the hands may be affected. Patients may develop difficulty walking because of discomfort, or because they have difficulty feeling their feet on the ground. Factors associated with increased risk of peripheral neuropathy include the following:

• Previous peripheral neuropathy
• Low CD4 count (<200 cells/µL)
• Previous AIDS-defining opportunistic infection or neoplasm
• Vitamin B12 deficiency
• Exposure to stavudine or didanosine
• Use of other drugs associated with peripheral neuropathy (e.g., isoniazid, dapsone, metronidazole, hydroxyurea, thalidomide, linezolid, ribavirin, vincristine)
• Use of other neurotoxic agents (e.g., alcohol)
• Diabetes mellitus

Patients should be assessed carefully before the introduction of a potentially neurotoxic medication (including stavudine or didanosine), and the use of these medications for patients at high risk of developing peripheral neuropathy should be avoided.

Pain is significantly undertreated, especially among HIV-infected women, because of factors ranging from providers' lack of knowledge about the diagnosis and treatment of pain to patients' fear of addiction to analgesic medications. Pain, as the so-called fifth vital sign, should be assessed at every patient visit.

S: Subjective

Self-report is the most reliable method to assess pain.

The patient complains of pain. The site and character of the pain will vary with the underlying cause. Ascertain the following from the patient:

• Duration, onset, progression
• Distribution, symmetry
• Character or quality (e.g., burning, sharp, dull)
• Intensity
• Severity (using the 0-10 scale; see Figure 1)
• Neurologic symptoms (e.g., weakness, cranial nerve abnormalities, bowel or bladder abnormalities)
• Exacerbating or relieving factors
• Response to current or past pain management strategies
• Past medical history (e.g., AIDS, diabetes mellitus)
• Psychosocial history
• Substance abuse and alcohol use history (amount, duration)
• Medications, current and recent (particularly zalcitabine, didanosine, stavudine, and isoniazid)
• Nutrition (vitamin deficiencies)
• Meaning of the pain to the patient

Measuring the severity of the pain: Have the patient rate the pain severity on a numeric scale of 0-10 (0 = no pain; 10 = worst imaginable pain), a verbal scale (none, small, mild, moderate, or severe), or a pediatric faces pain scale (when verbal or language abilities are absent). Note that pain ratings >3 usually indicate pain that interferes with daily activities. Use the same scale for evaluation of treatment response.

Figure 1. Faces Pain Rating Scale (0-10)

Quick screen for peripheral neuropathy: Ask about distal numbness and check Achilles tendon reflexes. Screening for numbness and delayed or absent ankle reflexes has the highest sensitivity and specificity among the clinical evaluation tools for primary care providers. For a validated screening tool, use the ACTG Brief Peripheral Neuropathy Scale (BPNS) to scale and track the degree of peripheral neuropathy.

O: Objective

Measure vital signs (increases in blood pressure, respiratory rate, and heart rate can correlate with pain). Perform a symptom-directed physical examination, including a thorough neurologic and musculoskeletal examination. Look for masses, lesions, and localizing signs. Pay special attention to sensory deficits (check for focality, symmetry, and distribution [such as "stocking-glove"]), muscular weakness, reflexes, and gait. Patients with significant motor weakness or paralysis, especially if progressive over days to weeks, should be evaluated emergently.

To evaluate peripheral neuropathy: Check ankle Achilles tendon reflexes and look for delayed or absent reflexes as signs of peripheral neuropathy. Distal sensory loss often starts with loss of vibratory sensation, followed by loss of temperature sensation, followed by onset of pain. Findings are usually bilateral and symmetric.

A: Assessment

Pain assessment includes determining the type of pain, for example, nociceptive, neuropathic, or muscle spasm pain.

Nociceptive pain occurs as a result of tissue injury (somatic) or activation of nociceptors resulting from stretching, distention, or inflammation of the internal organs of the body. It usually is well localized; may be described as sharp, dull, aching, throbbing, or gnawing in nature; and typically involves bones, joints, and soft tissue.

Neuropathic pain occurs from injury to peripheral nerves or central nervous system structures. Neuropathic pain may be described as burning, shooting, tingling, stabbing, or like a vise or electric shock; it involves the brain, central nervous system, nerve plexuses, nerve roots, or peripheral nerves. It is associated with decreased sensation and hypersensitivity.

Muscle spasm pain can accompany spinal or joint injuries, surgeries, and bedbound patients. It is described as tight, cramping, pulling, and squeezing sensations.

Although pain in HIV-infected patients often results from opportunistic infections, neoplasms, or medication-related neuropathy, it is important to include non-HIV-related causes of pain in a differential diagnosis. Some of these other causes may be more frequent in HIV-infected individuals. A partial list for the differential diagnosis includes:

• Anorectal carcinoma
• Aphthous ulcers
• Appendicitis
• Arthritis, myalgias
• Candidiasis, oral or esophageal
• Cholecystitis
• Cryptococcal disease
• Cytomegalovirus colitis
• Dental abscesses
• Gastroesophageal reflux disease (GERD)
• Ectopic pregnancy
• Herpes simplex
• Herpes zoster
• Kaposi sarcoma
• Lymphoma
• Medication-induced pain syndromes (e.g., owing to growth hormone, granulocyte colony-stimulating factor)
• Medication-induced peripheral neuropathy (e.g., owing to didanosine, stavudine, isoniazid, vincristine)
• Other causes of peripheral neuropathy: diabetes, hypothyroidism, B12 deficiency, syphilis, cryoglobulinemia (especially in patients with hepatitis C coinfection)
• Mycobacterium avium complex
• Myopathy
• Pancreatitis
• Pelvic inflammatory disease
• Toxoplasmosis

P: Plan

Perform a diagnostic evaluation based on the suspected causes of pain.

Treatment

Treatment should be aimed at eliminating the source of pain, if possible. If symptomatic treatment of pain is needed, begin treatment based on the patient's pain rating scale, using the least invasive route. The goal is to achieve optimal patient comfort and functioning (not necessarily zero pain) with minimal medication adverse effects, negotiated with the patient. Use the three-step pain analgesic ladder originally devised by the World Health Organization (WHO); see Figure 2.

Nonpharmacologic interventions

The following interventions can be used at any step in the treatment plan:

• A therapeutic provider-patient relationship
• Physical therapy
• Exercise
• Relaxation techniques
• Guided imagery
• Massage
• Biofeedback
• Reflexology
• Acupuncture
• Thermal modalities (hot and cold compresses or baths)
• Transcutaneous electrical nerve stimulation (TENS)
• Spiritual exploration
• Prayer
• Deep breathing
• Meditation
• Enhancement of coping skills
• Self-hypnosis
• Humor
• Distraction
• Hobbies

Pharmacologic interventions

Principles of pharmacologic pain treatment

• The dosage of the analgesic is adjusted to give the patient adequate pain control.
• The interval between doses is adjusted so that the pain control is uninterrupted. It can take 4-5 half-lives before the maximum effect of an analgesic is realized.
• Chronic pain is more likely to be controlled when analgesics are dosed on a continuous schedule rather than "as needed." Sustained-release formulations of opioids should be used whenever possible.
• For breakthrough pain, use "as needed" medications in addition to scheduled-dosage analgesics. When using opiates both for scheduled analgesia for breakthrough pain, a good rule of thumb is to use 10% of the total daily dosage of opiates as the "as needed" opiate dose for breakthrough pain.
• Oral administration has an onset of analgesia of about 20-60 minutes, tends to produce more stable blood levels, and is cheaper.
• Beware of the risk of prolonged analgesic half-lives in patients with renal or hepatic dysfunction.
• Caution when using combination analgesics that are coformulated with ingredients such as acetaminophen, aspirin, or ibuprofen. Determine the maximum daily dosage of all agents.

The following three steps are adapted from the WHO analgesic ladder. Agents on higher steps are progressively stronger pain relievers but tend to have more adverse effects.

Figure 2. Pharmacologic Approaches to Pain Management: WHO Three-Step Ladder

Adapted from World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health Organization; 1990.

Note: "Adjuvants" refers either to medications that are coadministered to manage an adverse effect of an opioid or to so-called adjuvant analgesics that are added to enhance analgesia.

Step 1: Nonopiates for mild pain (pain scale 1-3)

• The most common agents in this step include acetaminophen (650-1,000 mg PO Q6H as needed) and nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen 600-800 mg PO TID with food, and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib.
• A proton-pump inhibitor (such as omeprazole) can decrease the risk of gastrointestinal bleeding when using NSAIDs.
• Acetaminophen has no effect on platelets and no antiinflammatory properties; avoid use in patients with hepatic insufficiency, and in general limit to 4 g per day in acute use (or 2 g per day for patients with liver disease). Monitor liver function tests in chronic use.
• NSAIDs and acetaminophen can be used together for synergism.
• Note that COX-2 inhibitors have been associated with an increased risk of cardiovascular events and should be used with caution.

Step 2: Mild opiates with or without nonopiates for moderate pain (pain scale 4-6)

• Most agents used to treat moderate pain are combinations of opioids and Step 1 agents. The most common agents are acetaminophen combined with codeine, oxycodone, or hydrocodone. Codeine can be dosed as codeine sulfate, separately from acetaminophen. Beware of acetaminophen toxicity in these combination drugs.
• Other agents include buprenorphine (partial opiate agonist).
• Tramadol (Ultram) is a centrally acting nonopiate that can be combined with NSAIDs. As with opiates, it is prone to abuse. Tramadol lowers the seizure threshold; avoid use for patients with a seizure history. Avoid coadministration with selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) because of the risk of serotonin syndrome.

Step 3: Opioid agonist drugs for severe pain (pain scale 7-10)

• Morphine is the drug of choice in this step. Start with short-acting morphine and titrate the dosage to adequate pain control, then divide the 24-hour total in half to determine the dosing for the sustained-release morphine, given Q12H. When converting from IV to PO morphine, PO dosage is about two to three times the parenteral dose.
• Other agents used are oxycodone, hydromorphone, fentanyl, levorphanol, methadone, codeine, hydrocodone, oxymorphone, and buprenorphine.
• Avoid meperidine because of the increased risk of delirium and seizures.
• Around-the-clock, sustained-release PO dosing will achieve optimum pain relief.
• Patients unable to take PO therapy may use transdermal fentanyl patches or do rectal administration of sustained-release tablets such as long-acting morphine. Note that the onset of analgesia with fentanyl patches can take more than 12 hours, and the analgesic effect can last more than 18 hours after the patch is removed.
• Anticipate and treat complications and adverse effects of opioid therapy, such as nausea, vomiting, and constipation. Constipation often leads to nausea and can be prevented with prophylactic stool softeners (such as docusate) and stimulant laxatives (such as senna).

Adjunctive treatments

The addition of antidepressant medications can improve pain management, especially for chronic pain syndromes. These agents, and anticonvulsants, usually are used to treat neuropathic pain (discussed in more detail below), but should be considered for treatment of other chronic pain syndromes as well.

Treatment of neuropathic pain

Assess the underlying etiology, as discussed above, and treat the cause as appropriate. Review the patient's medication list for medications that can cause neuropathic pain. Discontinue the offending agents, if possible. For patients on stavudine or didanosine, in particular, switch to another nucleoside analogue if suitable alternatives exist, or at least consider dosage reduction of stavudine to 30 mg BID (consult with an HIV expert). For patients on isoniazid, ensure that they are taking vitamin B6 (pyridoxine) regularly to avoid isoniazid-related neuropathy.

Nonpharmacologic interventions for neuropathic pain

The nonpharmacologic interventions described above can be useful in treating neuropathic pain.

Pharmacologic interventions for neuropathic pain

Follow the WHO ladder of pain management described above. If Step 1 medications are ineffective, consider adding antidepressants, anticonvulsants, or both before moving on to opioid treatments.

Antidepressants

Antidepressant medications often exert analgesic effects at dosages that are lower than those required for antidepressant effects. As with antidepressant effects, optimum analgesic effects may not be achieved until several weeks after starting therapy.

• Tricyclic antidepressants (TCAs): Note that ritonavir and other protease inhibitors may increase the level of TCAs, so start at the lowest dosage and titrate up slowly. Dosages may be titrated upward every 3-5 days, as tolerated. In general, use lower dosages for elderly patients, up to 100 mg QHS.
  • Nortriptyline (Pamelor): Starting dosage is 10-25 mg QHS. Usual maintenance dosage is 20-150 mg QHS.
  • Desipramine (Norpramin): Starting dosage is 25 mg QHS. Usual maintenance dosage is 25-250 mg QHS.
  • Imipramine: Starting dosage is 25 mg QHS. Usual maintenance dosage is 25-300 mg QHS.
  • Amitriptyline (Elavil): Starting dosage is 10-25 mg QHS. Usual maintenance dosage is 25-150 mg QHS. Amitriptyline has the highest rate of adverse effects among the TCAs, so other agents typically are preferred.
  Adverse effects include sedation, anticholinergic effects (e.g., dry mouth, urinary retention), QT prolongation, arrhythmias, and orthostatic hypotension. Monitor TCA levels and EKG at higher dosage levels. There is a risk of overdose if taken in excess.
• SSRIs: See chapter Major Depression and Other Depressive Disorders for dosing, side effects, and drug interactions associated with this class of agents. SSRIs are less effective than TCAs in treating chronic pain.
• Venlafaxine (Effexor): Starting dosage is 37.5 mg daily. Usual maintenance dosage is 75-300 mg daily in divided doses or by extended-release formulation (Effexor XR). Note that there are limited data on using venlafaxine for patients with HIV infection.
• Duloxetine (Cymbalta): Starting dosage is 30-60 mg daily. Dosages of >60 mg per day are rarely more effective for either depression or pain treatment. Note that there are limited data on using duloxetine for patients with HIV infection.

Anticonvulsants

The following agents may be effective for neuropathic pain:

• Gabapentin (Neurontin): Considered first-line for HIV sensory neuropathy for its tolerability. Starting dosage is 100-300 mg QHS; may be increased every 3-5 days to BID or TID to achieve symptom relief. Monitor response and increase the dosage every 1-2 weeks by 300-600 mg/day. Usual maintenance dosage is 1,200-3,600 mg/day in divided doses. Adverse effects include somnolence, dizziness, fatigue, weight gain, and nausea. To discontinue, taper over the course of 7 or more days.
• Pregabalin (Lyrica): Starting dosage is 25-50 mg TID; may be increased by 25-50 mg per dose every 3-5 days as tolerated to achieve symptom relief. Maximum dosage is 200 mg TID. Adverse effects are similar to those of gabapentin. To discontinue, taper over the course of 7 or more days.
• Lamotrigine (Lamictal): Starting dosage is 25 mg QOD; titrate slowly to 200 mg BID over the course of 6-8 weeks to reduce the risk of rash (including Stevens-Johnson syndrome). Adverse effects include sedation,dizziness, ataxia, confusion, nausea, blurred vision, and rash. Note that lopinavir/ritonavir (Kaletra) may decrease lamotrigine levels; higher dosages may be needed. To discontinue, taper over the course of 7 or more days.
• Although phenytoin and carbamazepine have some effectiveness in treating neuropathy, they have significant drug interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, and their use with HIV-infected patients is limited. Topiramate and valproic acid have been used for migraine prophylaxis and anecdotally may be useful for treating peripheral neuropathy, but have not been well-studied in HIV-related neuropathies.

Treatment of Muscle Spasm Pain

Stretching, heat, and massage may help the pain of muscle spasm. This pain also can respond to muscle relaxants such as baclofen, cyclobenzaprine, tizanidine, benzodiazepines, as well as intraspinal infusion of local anesthetics for spinal injuries.

Substance Abuse, HIV, and Pain

Some health care providers hesitate to treat pain in patients with current or past substance abuse because of concern about worsening these patients' dependence on opioids or suspicion that such patients are seeking pain medications for illicit purposes. However, the following points should be considered:

• Many patients with current or past substance abuse do experience pain, and this pain should be evaluated by care providers and treated appropriately.
• Failure to distinguish among addiction, tolerance, and dependence can lead to undertreatment of chronic pain by health care providers.
• Addiction (substance abuse) is a complex behavioral syndrome characterized by compulsive drug use for the secondary gain of euphoria.
• Pharmacologic tolerance refers to the reduction of effectiveness, over time, of a given dosage of medication.
• Physical dependence is the consequence of neurophysiologic changes that take place in the presence of exogenous opioids.
• Aberrant use of pain medications, if it develops, is best managed by an interdisciplinary team of providers from HIV clinical care, psychiatry, psychology, pharmacy, social services, and drug addiction management.
• Drug-drug interactions between certain antiretroviral medications and methadone can decrease methadone serum concentrations (see chapter Drug-Drug Interactions with HIV-Related Medications). If this occurs, methadone dosages may need to be increased to prevent opiate withdrawal.
• As part of chronic pain management in patients with substance abuse, consider establishing a written pain-management contract to be signed by the clinician and the patient. The contract should:
  • Clearly state limits and expectations for both the patient and provider.
  • Identify a single clinician responsible for managing the pain regimen.
  • Tell the patient what to do if the pain regimen is not working.
  • Describe the procedure for providing prescriptions (e.g., one prescription given to the patient, in person, for a limited period of time, such as 1 month).
  • List the rules for dealing with lost medications or prescriptions.

Patient Education

• Pain management is part of HIV treatment, and patients should give feedback to allow the best treatment decisions. If pain persists for more than 24 hours at a level that interferes with daily life, patients should inform their health care provider so that the plan can be changed and additional measures, if needed, can be tried.
• Patients should not expect full pain relief in most cases, but enough relief that they can perform their daily activities.
• "Mild" pain medications (e.g., NSAIDs, aspirin, acetaminophen) usually are continued even after "stronger" medications are started because their mechanism of action is different from that of opiates. This combination of pain medication has additive effects, so that pain may be controllable with a lower narcotic dosage.
• Patients taking "around-the-clock" medications, should take them on schedule. Those taking "as needed" medications should take them between doses only if they have breakthrough pain.
• Opiates may cause severe constipation. Patients must remain hydrated and will likely need stool softeners, laxatives, or other measures. They should contact their health care provider promptly if constipation occurs.
• Patients should avoid use of recreational drugs and alcohol when taking opiates because opiates can interact with them or cause additive adverse effects, possibly resulting in central nervous system depression, coma, or death.
• Patients taking opiates should avoid driving and operating machinery.

http://www.aidsetc.org/aidsetc?page=cg-801_pain

All You Need To Know About Opioids And Pain Treatment

Today's important post from ncbi.nlm.nih.gov (see link below) will be of interest to all neuropathy patients who's lives have been so disrupted by the disease and the pain that it brings, that they have had no alternative but to use opioids to quell the symptoms. We go to the doctors and 99% of us dread hearing that opioids are the only remaining option but we have to do it in order to live reasonable daily lives. However, the explanation generally ends there. We know they're the strongest analgesics and we're well aware of the dangers of addiction, let alone the potential side effects but if you're between a rock and a hard place, you accept the prescription in good faith! This comprehensive article tells us all we need to know about these drugs and for that reason it can remove much of the anxiety associated with opioids. More than that, it provides the knowledge we need to justify to ourselves and others that although it may not be the solution of choice, it can be a very effective one. We also sign an invisible contract with the doctor to make sure that we are monitored and controlled throughout our use and any potential dangers are dealt with when they begin and not when they've taken hold. Definitely worth a read then for anyone in this situation - it's amazing how much better you feel when you have knowledge in your armory.

Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions
Andrew Rosenblum,1,* Lisa A. Marsch,1 Herman Joseph,1 and Russell K. Portenoy2
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Exp Clin Psychopharmacol
See other articles in PMC that cite the published article.
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Abstract

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic non-cancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainly about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.
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Introduction

Opioids play a unique role in society. They are widely feared compounds, which are associated with abuse, addiction and the dire consequences of diversion; they are also essential medications, the most effective drugs for the relief of pain and suffering (Portenoy et al, 2004). Historically, concerns about addiction have apparently contributed to the undertreatment of disorders widely considered to be appropriate for opioid therapy, including cancer pain, pain at the end-of-life, and acute pain (Field and Cassel, 1997; Schnoll & Weaver, 2003; Portenoy & Lesage, 1999; Breitbart et al. 1998; Smith et al., 2008). The use of opioids for chronic non-malignant pain (CNMP) remains controversial (Manchikanti, 2008; McQuay, 1999). Following publication of reports on the safety and efficacy of opioids prescribed to small numbers of patients with CNMP (e.g., Portenoy and Foley, 1986; Nyswander and Dole, 1986) and the publication of a seminal article entitled “The Tragedy of Needless Pain”, (Melzack, 1990), the use of opioids to treat CNMP began to be more widely practiced and incorporated into clinical guidelines. Nevertheless, despite the advances in pain medicine and the wider use of opioids for various chronic pain conditions, there is still considerable controversy surrounding the type of conditions that should be treated, whether the treatment can be generally safe and effective in selected patients, and what the clinical goals should be (Ballantyne & Forge, 2007; Streltzer & Johansen, 2006; Stretzler & Kosten 2003).
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History of Opioids

The Sumerians in Mesopotamia were among the first people identified to have cultivated the poppy plant around 3400 BC. They named it Hul Gil, the “joy plant” (Booth, 1986). It eventually spread throughout the ancient world to every major civilization in Europe and Asia and was used to treat pain and many other ailments (Schiff, 2002; Askitopoulou, Ramoutsaki, & Konsolaki, 2002; Booth, 1986; Dikotter, Laaman, & Xun, 2004).


Developments in the 19th century transformed the practice of medicine and initiated the tension between the desire to make available the medicinal benefits of these drugs and recognition that the development of abuse and addiction can lead to devastating consequences for individuals and for society at large (Booth, 1986; Musto, 1999):
In 1803 morphine, an opioid analgesic, was extracted from opium by Friedrich Serturner of Germany;
Dr. Charles Wood, a Scottish physician, invented the hyperdermic needle and used it to inject morphine to relieve pain from neuralgia;
Dr. Eduard Livenstein, a German physician, produced the first accurate and comprehensive description of addiction to morphine, including the withdrawal syndrome and relapse, and argued that craving for morphine was a physiological response.
Diacetylmorphine (brand name heroin) was synthesized and briefly promoted as more effective and less addictive than morphine. In the early 20th century, when heroin was legally marketed in pill form, it was used by young Americans to elicit intense euphoria by crushing the heroin pills into powder for inhalation or injection (Katz et al., 2007, c.f. Meldrum, 2003; Hosztafi, 2001).

Beginning in the twentieth century, there were many research advances and major changes in the way opioids were used for the treatment of pain and addiction (Ballantyne, 2006; Corbett et al., 2006). These included attempts among several nations and international organizations to control the distribution and use of opioids (Musto, 1999); the introduction of opioid maintenance therapy for the treatment of opioid addiction (first with morphine and later with methadone, LAAM (levo-alpha acetyl methadol) and sublingual buprenorphine) (Courtwright, Joseph & Des Jarlais, 1989; Strain & Stitzer, 2006); the discovery of the endogenous opioids (Hughes, Smith, Kosterlitz, Fothergill, Morgan & Morris, 1975); and the recognition that pain is a debilitating and destructive disease and that opioids are essential for the treatment of many forms of acute and chronic pain.

During most of the twentieth century, the widely held perception among professionals in the United States was that the long-term use of opioid therapy to treat chronic pain was contraindicated by the risk of addiction, increased disability and lack of efficacy over time. During the 1990’s, a major change occurred, driven by a variety of medical and nonmedical factors (see below). The use of opioids for chronic pain began to increase, showing a substantial year-to-year rise that continues today. This increased use of opioids for legitimate medical purposes has been accompanied by a substantial increase in the prevalence of nonmedical use of prescription opioids (Zacny, et al., 2003). The National Survey on Drug Use and Health reported that the number of first time abusers of prescription opioids increased from 628,000 in 1990 to 2.4 million in 2004, that emergency room visits involving prescription opioid abuse increased by 45% from 2000 to 2002, and that treatment admissions for primary abuse of prescription opioids increased by 186% between 1997 and 2002 (SAMHSA, 2004a, 2004b). Opioid abuse indices rose most for two frequently prescribed opioids, hydrocodone and controlled-release (CR) oxycodone (Cicero, Inciardi, Munoz, 2005). Although the increase in prescription drug abuse is likely to be multifactorial, it is likely to reflect, in part, changes in available drug formulations and prescribing practices of opioid medication (Compton and Volkow, 2006). This link between increased medical use and increased abuse has driven some of the re-examination of the medical role of these drugs. The challenge, of course, is to reduce the likelihood of opioid misuse while not imposing barriers on the legitimate use of opioid medications, acknowledging both that increased abuse is probably inevitable when a psychoactive drug becomes more accessible and that attempts to control abuse can have the unintentional effects of discouraging treatment and placing severe restrictions on the medical profession.
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Brief Overview of Opioids: Neurobiology and Mechanism of Action

The term opioid refers to all compounds that bind to opiate receptors. Conventionally, the term opiate can be used to describe those opioids that are alkaloids, derived from the opium poppy; these include morphine and codeine. Opioids include semi-synthetic opiates, i.e., drugs that are synthesized from naturally occurring opiates (such as heroin from morphine and oxycodone from thebaine), as well as synthetic opioids such as methadone, fentanyl, and propoxyphene. The term narcotic is a legal designation and should not be used in the clinical setting; it refers to opioids and a few other drugs that are grouped with the opioids by law enforcement.

In the United States, numerous opioids have been commercialized for oral, transdermal and intravenous administration. Oral and transdermal formulations are usually administered for pain in the ambulatory setting. These include combination products, such as those containing hydrocodone and acetaminophen (Vicodin®, Lorset®) or ibuprofen (Vicoprofen®), tramadol and acetaminophen (Ultracet®), oxycodone and acetaminophen or aspirin (Percocet® or Percodan®), and those containing codeine and acetaminophen or aspirin. The single entity formulations on the market include those containing morphine (Avinza®, Kadian®, MS Contin®, MSIR®), oxycodone (OxyContin®), fentanyl (Duragesic®, Actiq®, Fentora®), hydromorphone (Dilaudid®), oxymorphone (Opana®), and methadone.

Opioids act by binding to specific proteins, called opioid receptors. Receptors are widely distributed. Those involved in pain modulation are situated in both the central nervous system and the peripheral nervous system. These receptors also bind endogenous opioid peptides (endorphins), which are involved in pain modulation and numerous other functions in the body. Among these functions are those mediated by deep structures of the brain, which are involved in the modulation of reinforcement and reward mechanisms, mood and stress. Opioid receptors are also found on cells from the immune system (Bidlack, 2000). In studies with rats, activation of these receptors with morphine is associated with varied effects, including sensitization of afferent nerves to noxious stimuli (Raghavendra, Rutkowski, & DeLeo, 2002).

When an opioid given for pain binds to receptors, analgesia may be accompanied by any of a diverse array of side effects related to the activation of receptors involved in other functions. These may include effects mediated by peripheral or by peripheral and central mechanisms, such as reduced peristalsis (leading to constipation) and itch, or primary central nervous system effects, such as miosis, (pupillary constriction) somnolence, mental clouding, and respiratory depression (Jaffe & Jaffe, 2004; Jaffe & Martin, 1990). Central mechanisms also lead to changes associated with hyperalgesia and decreased responsiveness to opioids (tolerance) and it has been speculated that opioid-induced hyperalgesia may be a clinically-relevant phenomenon leading to increased pain in some situations (Deleo, Tanga, & Tawfik, 2004). Activation of other central nervous system pathways by opioids also may produce mood effects, either dysphoria or euphoria.

Presumably, binding to those receptors involved in reinforcement and reward also occurs whenever an opioid is taken. In most individuals, when opioids are taken to treat pain, there appears to be no overt effect from change in these systems. In some cases, however, powerful reinforcement occurs, expressed as efforts to repeat the administration and these reinforcing outcomes may be associated with craving and with positive mood effects such as euphorigenic or pleasurable effects (Di Chiara, 2002; Koob & Bloom, 1988). These outcomes, which are uncommon but potentially serious when they occur (driving the development of an addictive pattern of use), can occur in the presence or absence of pain. Although these effects could be associated with iatrogenic addiction, they appear to be rare in patients who do not have risk factors suggesting the existence of the biological substrate for opioid-induced craving (see below).

Although several types of opioid receptors exist (e.g., mu, kappa and delta), opioid drugs largely produce their analgesic and reinforcing effects via activation of the mu opioid receptor; thus, opioids used for pain are often described as, “mu agonists”. Mu drugs that have the ability to fully activate opioid receptors (e.g., higher doses produce greater receptor activation in a dose-dependent manner) are referred to as opioid agonists or full mu agonists (such as morphine, oxycodone and methadone). Those opioids that occupy, but do not activate, receptors are referred to as opioid antagonists (e.g., naltrexone, naloxone); they can reverse the effects of mu opioid agonists. Those opioids that either have a low intrinsic activity at the mu receptor, or are agonists at another receptor and antagonists at the mu receptor are called agonist-antagonist drugs. Those with a low intrinsic activity are called partial opioid agonists and are characterized by a ceiling on most agonist activity, such that increases in dose will increase the drug’s physiological and subjective effects only to a certain level and further dose increases produce no additional effects (Jaffe & Martin, 1990).

These differences in mu receptor interactions are clearly related to the clinical use of opioid drugs and their abuse liability. Agonist-antagonist drugs are less attractive than pure mu agonists to individuals with addiction and no pain. Although other biochemical and molecular processes are presumably relevant to variation in these effects, relatively little is known about the interactions among these processes in humans.

The clinical use of opioid drugs is influenced by a variety of other characteristics, including pharmacokinetics. With the notable exception of methadone and buprenorphine, most opioids have relatively short half-lives and this has necessitated the development of new delivery systems designed to provide prolonged effects and a longer dosing interval.

Clinically-relevant physical dependence and tolerance (see below) may occur with short-term or long-term use of an opioid compound, particularly a pure mu agonist. These phenomena, which vary greatly in the clinical setting, represent neuroadaptational processes. The neurophysiology of physical dependence and tolerance are closely related to each other and to the phenomenon of opioid-induced hyperalgesia (Mao, 2002). The possibility that opioid administration, particularly at relatively high doses, may lead to increased pain has contributed to the controversy about opioid therapy for non-cancer pain, notwithstanding the limited evidence that this phenomenon occurs in clinical settings.
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Brief Overview of Chronic Pain

Chronic pain has been described as pain that has persisted for at least 1 month following the usual healing time of an acute injury, pain that occurs in association with a nonhealing lesion, or pain that recurs frequently over a period of months. In most clinical and research reports, chronic pain is typically defined as pain that has persisted for at least 3 months (Verhaak, Kerssens, Dekker, Sorbi, & Sensing, 1998).

The prevalence of chronic pain in the general population is believed to be quite high, although published reports have varied greatly. Cautious cross-national estimates of chronic pain range from 10% (Verhaak et al., 1998) to close to 20% (Gureje, Simon, & Von Korff, 2001), which would represent 30 to 60 million Americans. A national survey of 35,000 households in the US, conducted in 1998, estimated that the prevalence among adults of moderate to severe non-cancer chronic pain was 9% (American Pain Society, 1999). A large survey (N=18,980) of general populations across several European countries reported that the prevalence for chronic painful physical conditions was 17.1% (Ohayon & Schatzberg, 2003).

Chronic pain is a highly complex phenomenon, which may or may not be primarily driven by tissue injury. Conventionally, the most common forms of chronic pain are divided into those labeled “nociceptive”, or pain caused by ongoing stimulation of pain receptors by tissue damage, and those labeled “neuropathic”, or pain presumed to be related to damage to or dysfunction of the peripheral or central nervous system. These categories of pain simplify a complex reality in which both acute and chronic pain are induced by multiple peripheral and central mechanisms, which continually interact with each other and with numerous pain modulating systems. The perturbations that ultimately results in pain perception are caused by neurophysiological processes and other related systems. For example, recent evidence has begun to highlight the role of neuroimmune activation following a tissue injury as an important mechanism in the development of chronic pain (DeLeo, 2006). The role of cytokines and other inflammatory mediators is obvious in inflammatory nociceptive pains, such as some types of arthritis, but new data suggest an equally salient role in the development of chronic neuropathic pain associated with central sensitization of neural pathways following peripheral injury (Deleo, 2006).

All chronic pain is profoundly influenced by psychological processing and responses (Turk & Melzack, 2001). Pain severity and pain-related functional impairment are often found to be associated with psychological and social factors, and patients with identical diseases associated with pain, such as degenerative disk disease, may vary greatly in their reports of pain severity and pain behaviors (Aronoff, 1999). There is an extensive literature documenting the importance of operant conditioning factors (Fordyce, 1976) and cognitive-behavioral factors (Turk, Meichenbaum, & Genest, 1983) in the maintenance of chronic pain behaviors.

Chronic pain also is influenced by psychosocial and psychiatric disturbances, such as cultural influences, social support, comorbid mood disorder, and drug abuse (Gatchel, Peng, Peters, Fuchs & Turk, 2007). Classic studies of pain behavior indicate that cultural differences in the beliefs and attitudes towards pain (e.g., Zbrowski, 1969) and the social/environmental context of the pain (e.g., Beecher, 1959) have a significant impact on pain behaviors.

The contribution of psychological, social and psychiatric factors should not lead to the conclusion that a pain syndrome is primarily psychogenic. Pain related exclusively or primarily to psychological factors occurs, but is far less prevalent than pain associated with organic processes that are powerfully influenced by psychosocial mediators and psychiatric comorbidities (Portenoy, Payne, & Passik, 2004).

The “pattern of suffering” or the pain-related disability that often occurs in concert with persistent pain commonly touches on all domains of function. Patients with chronic pain may demonstrate pain-related interference with ability to perform usual activities at home, work, or school; maladaptive or dysfunctional behaviors, social isolation, and poor sleep patterns; and frequent health care utilization (Dworkin & Sherman, 2001). The recognition that acute pain can compromises health has led major medical associations and accreditation committees to designate pain severity as a “fifth vital sign”, along with blood pressure, temperature, heart rate, and respiration (Fishman, 2005). Further recognition of the increased interest in the assessment and management of pain is underscored by the U.S. Federal Law (Pain Relief Promotion Act of 2000) that declared the first decade of the 21st century as the Decade of Pain Control and Research (Gatchel et al., 2007).

Chronic pain is a major public health problem, which is associated with devastating consequences to patients and families, a high rate of health care utilization, and huge society costs related to lost work productivity. The existing treatments for chronic pain are unable to address the problem and better therapies are urgently needed. The need for these therapies is the backdrop for the expanding use of opioid drugs. An extensive clinical experience indicates that long-term opioid therapy is able to help selected patients have a better quality of life, less use of health care, and improved productivity. The medical community is no longer debating the reality of these outcomes, but rather, is now focused on a more fruitful debate about patient selection and the benefits and burdens of these drugs in varied subpopulations. Whether the frame of reference is the individual patient and family, or society-at-large, the issue is about balancing the potential benefits of these drugs in the large and diverse population with chronic pain with its potential risks.
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Terminology of Opioid Abuse: Dependence, Tolerance, Addiction

Concerns that addiction is a frequent iatrogenic consequence of the medical use of opioids may partially be attributed to confusion over terminology, as a well as failure to recognize that both addiction and chronic pain have a multifactorial etiology. In an effort to develop universal agreement on terminology related to addiction, the American Academy of Pain Medicine (AAPM), the American Pain Society (APS), and the American Society of Addiction Medicine (ASAM) approved a consensus document that clarified this terminology (ASAM, 2001; Savage, 2003).

According to the consensus document, tolerance is defined as a decreased subjective and objective effect of the same amount of opioids used over time, which concomitantly requires an increasing amount of the drug to achieve the same effect. Although tolerance to most of the side effects of opioids (e.g., respiratory depression, sedation, nausea) does appear to occur routinely, there is less evidence for clinically significant tolerance to opioids– analgesic effects (Collett, 1998; Portenoy et al., 2004). For example, there are numerous studies that have demonstrated stable opioid dosing for the treatment of chronic pain (e.g., Breitbart, et al., 1998; Portenoy et al., 2007) and methadone maintenance for the treatment of opioid dependence (addiction) for extended periods (Strain and Stitzer, 2006). However, despite the observation that tolerance to the analgesic effects of opioid drugs may be an uncommon primary cause of declining analgesic effects in the clinical setting, there are reports (based on experimental studies) that some patients will experience worsening of their pain in the face of dose escalation (Ballantyne, 2006). It has been speculated that some of these patients are not experiencing more pain because of changes related to nociception (e.g. progression of a tissue-injuring process), but rather, may be manifesting an increase in pain as a result of the opioid-induced neurophysiological changes associated with central sensitization of neurons that have been demonstrated in preclinical models and designated opioid-induced hyperalgesia (Mao, 2002; Angst & Clark, 2006). Analgesic tolerance and opioid-induced hyperalgesia are related phenomena, and just as the clinical impact of tolerance remains uncertain in most situations, the extent to which opioid-induced hyperalgesia is the cause of refractory or progressive pain remains to be more fully investigated. Physical dependence represents a characteristic set of signs and symptoms (opioid withdrawal) that occur with the abrupt cessation of an opioid (or rapid dose reduction and/or administration of an opioid antagonist). Physical dependence symptoms typically abate when an opioid is tapered under medical supervision. Unlike tolerance and physical dependence which appear to be predictable time-limited drug effects, addiction is a chronic disease that “represents an idiosyncratic adverse reaction in biologically and psychosocially vulnerable individuals” (ASAM, 2001).

The distinction between physical dependence and addiction is not always made clear in the pain literature (Ferrell, McCaffery, Rhiner, 1992). Most patients who are administered opioids for chronic pain behave differently from patients who abuse opioids and do not ever demonstrate behaviors consistent with craving, loss of control or compulsive use (e.g., Cowan et al., 2001). Of course, pain and addiction are not mutually exclusive and some patients who are treated for pain do develop severe behavioral disturbances indicative of a comorbid addictive disorder.

Some patients who are treated with opioids for pain display problematic behaviors that, on careful assessment, do not reflect addiction, but rather, appear to relate to a different process. This may be another psychiatric disorder associated with impulsive drug-taking, an unresolved family issue, a disorder of cognition, or criminal intention. In addition, there appear to be some patients who engage in problematic behaviors related specifically to desperation about unrelieved pain. The term pseudoaddiction was coined to describe the latter phenomenon (Weissman & Haddox, 1989).

Behaviors that may represent pseudoaddiction and behaviors that reflect addiction or some other serious psychopathology can occur simultaneously, and presumably, one type of phenomenon may incite the others. The diagnosis of these and other conditions may be challenging and requires a careful assessment of clinical phenomenology, specifically a range of drug-related behaviors during treatment with a potentially abusable drug (Portenoy, 1994, Lue, Passik, & Portenoy, 1998).

The term aberrant drug-related behaviors has been used to indicate the broad array of problematic nonadherence behaviors (Passik, Kirsh, Donaghy, & Portenoy, 2006), the nature of which is uncertain until a diagnosis can be developed based on astute clinical assessment. Some aberrant drug-related behavior strongly suggests the existence of addiction. These may include the use of alternative routes of administration of oral formulations (e.g., injection or sniffing), concurrent use of alcohol or illicit drugs, and repeated resistance to changes in therapy despite evidence of adverse effects; examples of aberrant behavior less suggestive of addiction are drug hoarding during periods of reduced symptoms, occasional unsanctioned dose escalation, and aggressive complaining about the need for more drugs (Portenoy, 1994).
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Distinction between Withdrawal and Chronic Pain

Because addiction is associated with psychological distress and physical discomfort in the form of opioid withdrawal symptoms, it may be difficult to distinguish primary chronic pain complaints from withdrawal pain. Withdrawal also may have the potential to increase baseline pain related to other processes. For example, based on anecdotal evidence from chronic pain patients, withdrawal from opioids can greatly increase pain in the original pain site. These phenomena suggest the need to carefully assess the potential for withdrawal during long-term opioid therapy (e.g, at the end of a dosing interval or during periods of medically-indicated dose reduction).

These phenomena notwithstanding, there also is evidence that experienced drug abusers are able to distinguish withdrawal pain from chronic pain. For example in studies of methadone maintenance patients, both the phenomenology and correlates of chronic pain were different than for withdrawal pain (Karasz et al., 2004; Rosenblum et al., 2003). Chronic pain is typically localized (e.g., back pain, headache) and persists (although with varying degrees of severity) for long periods of time (Gureje, Von Korff, Simon & Gater, 1998). Although certain subjective experiences of withdrawal (e.g., muscle ache) are similar to some distinct pain syndromes, other withdrawal experiences such as yawning, sweating and hot and cold flashes are likely to be more commonly associated with subjective drug withdrawal than with primary pain conditions. Moreover, the constellation of words used to describe withdrawal pain is likely to be different than words used to describe other painful disorders. Qualitative studies of addicts going through withdrawal typically refer to the experience as “being sick” (similar to a moderate to severe flu-like illness) and not as representing a distinct pain (Farrell, 1994). The subjective experience of withdrawal can be validly measured with an instrument such as the Subjective Opiate Withdrawal Scale (SOWS; Handelsman, et al., 1987). Withdrawal from short-acting opioids, such as heroin, is typically short-lived; physical symptoms are likely to reach their maximum intensity over a 36–72 hour period and to reduce in intensity after that (Farrell, 1994).
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Co-occuring Chronic Pain and Opioid Addiction

The prevalence of addictive disorders among chronic pain patients is difficult to determine (Covington and Kotz 2003). One 1992 literature review found only seven studies that utilized acceptable diagnostic criteria and reported that estimates of substance use disorders among chronic pain patients ranged from 3.2% – 18.9% (Fishbain, Rosomoff, & Rosomoff, 1992). A Swedish study of 414 chronic pain patients reported that 32.8% were diagnosed with a substance use disorder (Hoffmann, Olofsson, Salen, & Wickstrom, 1995). In two US studies, 43 to 45% of chronic pain patients reported aberrant drug-related behavior; the proportion with diagnosable substance use disorder is unknown (Katz et al., 2003; Passik et al., 2004). All these studies evaluated patients referred to pain clinics and may overstate the prevalence of substance abuse in the overall population with chronic pain.

A relatively high prevalence of substance abuse disorders among persons with chronic pain can also be inferred by the high co-occurrence of these two disorders. There have been several reports that the prevalence of chronic pain among persons with opioid and other substance use disorders is substantially higher than the pain prevalence found in the general population (Breitbart, et al., 1996; Brennan, Schutte, & Moos, 2005; Jamison, Kauffman, & Katz, 2000; Rosenblum et al., 2003; Sheu, et al., 2008).
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Opioid Treatment for Chronic Pain

Opioid therapy is the mainstay approach for the treatment of moderate to severe pain associated with cancer or other serious medical illnesses (Patt & Burton, 1998; World Health Organization, 1996). Although the use of opioid analgesics for the treatment of CNMP has been increasing in recent years (Joranson, Ryan, Gilson & Dahl, 2000) and has been endorsed by numerous professional societies (AAPM, APS, 1997; American Geriatric Society, 1998; Pain Society, 2004), the use of opioids remains controversial due to concerns about side effects, long-term efficacy, functional outcomes, and the potential for drug abuse and addiction. The latter concerns are especially evident in the treatment of CNMP patients with substance use histories (Savage, 2003).

Other concerns that may contribute to the hesitancy to prescribe opioids may be related to perceived and real risks associated with regulatory and legal scrutiny during the prescribing of controlled substances (Office of Quality Performance, 2003). These concerns have propelled extensive work to develop predictors of problematic behaviors or frank substance abuse or addiction during opioid therapy. Questionnaires to assist in this prediction and monitoring have been developed and used in research and field trials. Examples include the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 1998); the Pain Assessment and Documentation Tool (PADT; Passik et al., 2004) and the Current Opioid Misuse Measure (COMM; Butler et al., 2007). These instruments are not used in practice settings at this time.

Narrative reports on the use of opioids for CNMP have underscored the effectiveness of opioid therapy for selected populations of patients and there continues to be a consensus among pain specialists that some patients with CNMP can benefit greatly from long-term therapy (Ballantyne & Mao, 2003; Trescot et al., 2006). This consensus, however, has received little support in the literature. Systematic reviews on the use of opioids for diverse CNMP disorders report only modest evidence for the efficacy of this treatment (Trescot et al., 2006; 2008). For example, a review of 15 double-blind, randomized placebo-controlled trials reported a mean decrease in pain intensity of approximately 30% and a drop-out rate of 56% only three of eight studies that assessed functional disturbance found improvement (Kalso, Edwards, Moore, & McQuay, 2004). A meta-analysis of 41 randomized trials involving 6,019 patients found reductions in pain severity and improvement in functional outcomes when opioids were compared with placebo (Furlan, Sandoval, Mailis-Gagnon, & Tunks, 2006). Among the 8 studies that compared opioids with non-opioid pain medication, the six studies that included so-called “weak” opioids (e.g., codeine, tramadol) did not demonstrate efficacy, while the two that included the so-called “strong” opioids (morphine, oxycodone) were associated with significant decreases in pain severity. The standardized mean difference (SMD) between opioid and comparison groups, although statistically significant, tended to be stronger when opioids were compared with placebo (SMD = 0.60) than when strong opioids where compared with non-opioid pain medications (SMD = 0.31). Other reviews have also found favorable evidence that opioid treatment for CNMP leads to reductions in pain severity, although evidence for increase in function is absent or less robust (Chou, Clark, & Helfand, 2003; Eisenberg, McNicol, & Carr, 2005). Little or no support for the efficacy of opioid treatment was reported in two systematic reviews of chronic back pain (Deshpande, Furlan, Mailis-Gagnon, Atlas, & Turk, 2007; Martell, et al., 2007). Because patients with a history of substance abuse typically are excluded from these studies, they provide no guidance whatsoever about the effectiveness of opioids in these populations.

Adding further to the controversy over the utility of opioid analgesics for CNMP is the absence of epidemiological evidence that an increase in the medical use of opioids has resulted in a lower prevalence of chronic pain. Noteworthy is a Danish study of a national random sample of 10,066 respondents (Eriksen, Sjøgren, Bruera, Ekholm, & Rasmussen, 2006). Denmark is known for having an extremely high national usage of opioids for CNMP and this use has increased by more than 600% during the past two decades (Eriksen, 2004). Among respondents reporting pain (1,906), 90% of opioid users reported moderate to very severe pain, compared with 46% of non-opioid users; opioid use was also associated with poor quality of life and functional disturbance (e.g., unemployment).

Although this epidemiological study may be interpreted as demonstrating that opioid treatment for CNMP has little benefit, the authors acknowledge that these disquieting findings do not indicate causality and could be influenced by the possibility of widespread undertreatment, leading to poorly managed pain. This latter interpretation is supported by a commentary on the Ericksen et al. study (Keane, 2007). Keane notes that among the 228 pain patients receiving opioids only 57 (25%) were using strong opioids, while the remainder was using weak opioids. European (as well as United States) clinical guidelines generally recommend long-acting formulations of strong opioids for the treatment of chronic moderate to severe pain, which may be supplemented with short-acting opioids for breakthrough pain (Pain Society, 2004; OQP, 2003; Gourlay, 1998; Vallerand, 2003; Fine & Portenoy, 2007).

The possibility of inappropriate opioid treatment is further supported by another Danish study that assigned pain patients who were on opioid therapy to either a multidisciplinary pain center (MPC) or to general practitioners (GP) who had received initial supervision from the MPC staff (Eriksen, Becker, & Sjegren, 2002). At intake, a substantial number of patients in both groups were apparently receiving inappropriate opioid therapy for chronic pain (60% were being treated with short-acting opioids and 49% were taking opioids on demand). At the 12 month follow-up, 86% of MPC patients were receiving long-acting opioids and 11% took opioids on demand. There was no change in the administration pattern in the GP group. These findings suggest that a significant proportion of opioid-treated CNMP patients may be receiving inappropriate opioid treatment and that educating general practitioners in pain medicine may require more than initial supervision.

It is generally acknowledged that there is a wide degree of variance in the prescribing patterns of opioids for chronic pain (Lin, Alfandre, & Moore, 2007; Trescot et al., 2006). Some opioid treatment practices persist despite evidence that they might be harmful or have little benefit, such as the over-prescribing of propoxyphene among the elderly (Barkin, Barkin, & Barkin, 2006; Singh, Sleeper, & Seifert, 2007). Nursing home patients being treated with opioids have been found to be inadequately assessed for pain and to be more likely treated with short-acting rather than long acting opioids (Fujimoto & Coluzzi, 2000). A substantial number of physicians are reluctant or unwilling to prescribe long-acting opioids to treat CNMP, even when it may be medically appropriate (Nwokeji, et al., 2007).

Controversy about the long-term effectiveness of opioid treatment also has focused on the potential clinical implications of opioid-induced hyperalgesia. As noted earlier, exposure to opioids can result in an increased sensitivity to noxious stimuli in animals, and an increased perception of some types of experimental pain in humans (c.f., Koppert & Schmeltz, 2007; Angst & Clark, 2006). Anecdotal reports of hyperalgesia occurring with very high or escalating doses of opioids (Angst & Clark, 2006) has been viewed as a clinical correlate of these experimental findings. The extent to which this phenomenon is relevant to the long-term opioid therapy administered to most patients with chronic pain is unknown. Although experimental evidence suggests that opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain (Chu, Clark, & Angst., 2006), there have been no reports of observations in the clinical literature to suggest that it should be a prominent problem. More research is needed to determine whether the physiology underlying opioid-induced hyperalgesia may be involved in a subgroup of patients who develop problems during therapy, such as loss of efficacy (tolerance) or progressive pain in the absence of a well defined lesion.

Outcome studies of long term use of opioids are compromised by methodological limitations which make it difficult to acquire evidence of efficacy (Noble, Tregear, Treadwell, & Schoelles, 2007). Methodological limitations may be unavoidable because of the ethical and practical challenges associated rigorous studies such as randomized controlled trials. Guidelines for opioid therapy must now be based on limited evidence; future evidence may be acquired by utilizing other study designs (Noble et al., 2007) such as practical clinical trials (Tunis, Stryer, & Clancy, 2003). These studies should include at least three criteria to reflect a positive treatment response: i.e., reduction of pain severity (derived from subjective reports or scores on pain scales), recovery of function (improved scores on instruments that measure some aspect of function), and quality of life.

Guidelines for the use of opioids for the treatment of chronic pain have been published (AAFP et al., 1996–2002; OQP, 2003), and recent guidelines have emphasized the need to initiate, structure and monitor therapy in a manner that both optimizes the positive outcomes of opioid therapy (analgesia and functional restoration) and minimize the risks associated with abuse, addiction and diversion (Portenoy et al., 2004). These guidelines discuss patient selection (highlighting the likelihood of increased risk among patients with prior histories of substance use disorders), the structuring of therapy to provide an appropriate level of monitoring and a presumably lessened risk of aberrant drug-related behavior, the ongoing assessment of drug-related behaviors and the need to reassess and diagnose should these occur, and strategies that might be employed in restructuring therapy should aberrant behaviors occur and the clinician decide to continue treatment. They also note that therapy should be undertaken initially as a trial, which could lead to the decision to forego more therapy, and that an “exit strategy” must be understood to exist should the benefits in the individual be outweighed by the burdens of treatment.

The relatively recent recognition that guidelines for the opioid treatment of chronic pain must incorporate both the principles of prescribing as well as approaches to risk assessment and management may represent an important turning point for this approach to pain management. Acknowledging that prescription drug abuse has increased during the past decade, a period during which the use of opioid therapy by primary care physicians and pain specialists has accelerated, pain specialists and addiction medicine specialists now must collaborate to refine guidelines, help physicians identify the subpopulations that can be managed by primary care providers, and discover safer strategies that may yield treatment opportunities to larger numbers of patients.
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Treating Patients with Addictive Disorders

Safe and effective pain treatment is especially important for persons with a drug use history because inadequate treatment or lack of treatment for pain may have problematic consequences, such as illicit drug use (e.g., heroin), misuse of prescription opioids and other pain medications (e.g., benzodiazipines), psychiatric distress, functional impairment and a tendency for health providers to attribute pain complaints and requests for pain medication to an addictive disorder rather than to a pain disorder (Gureje, et al., 2001; Scimeca, Savage, Portenoy, & Lowinson, 2000). Undertreatment of pain among addicted persons may lead to the adverse medical, social and personal consequences associated with continued drug-seeking behavior (Savage, 1996). Pain complaints may be most problematic among persons with opioid addiction, as this group may have lower tolerance for pain than other addicted populations (Compton, 1994; Compton, Charuvastra, & Ling, 2001). Pain and opioid addiction may be further intertwined among persons who have a history of abusing controlled opioid pain medications, such as oxycodone or hydrocodone.
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A Possible Role on the use of Buprenorphine for the Treatment of Chronic Pain

Increasing interest in developing clinical protocols for opioid treatment of chronic pain in the population with substance abuse histories has highlighted the role of opioid medications that may have lower abuse potential. One medication that is beginning to be examined is buprenorphine, a partial opioid mu agonist that is well recognized as an analgesic (Johnson, Fudala, & Payne, 2005). In 2002, a sublingual tablet (both in mono form – Subutex® - and combined with naloxone - Suboxone®) was approved by the U.S Food and Drug Administration as a Schedule III medication for the treatment of opioid dependence. In numerous controlled clinical trials, it has been demonstrated to be highly efficacious in reducing illicit opioid use and promoting treatment retention among opioid abusers (e.g., Johnson, Strain, & Amass, 2003; Kakko, Svanborg, Kreek, Heilig, 2003; O'Connor et al., 1998; Fudala et al., 2003). In opioid addicts, it suppresses the craving and withdrawal symptoms associated with opioid use and also blocks the euphoric effects of subsequent opioid use (See Bickel & Amass, 1995 for a review).

As a partial mu-agonist, buprenorphine has a ceiling effect on its agonist activity (Lewis, 1985; Walsh, Preston, Bigelow & Stitzer, 1995). It is less likely than a full agonist to cause respiratory depression in opioid-naïve patients (Cowan, Lewis & Macfarlane, 1977). This property of buprenorphine increases its safety profile by reducing the risk of accidental overdose (Walsh, Preston, Stitzer, Cone & Bigelow, 1994). The partial agonism of buprenorphine would presumably yield a ceiling effect for analgesia as well, which would limit the clinical use of the drug in pain management, but there is some question about the extent of this ceiling effect in practice (Dahan, et al., 2006).

Although the combination buprenorphine/naloxone tablet (Suboxone) may precipitate withdrawal in opioid-tolerant persons if it is injected, making it relatively unattractive for diversion (CSAT, 2004), there is nevertheless evidence of diversion, as would be expected with any psychoactive drug that has hedonic properties (Cicero & Inciadi, 2005; Smith, Bailey, Woody, & Kleber, 2007). Rates of abuse are relatively low compared to full mu agonists and buprenorphine rarely is endorsed as a primary drug of abuse (Cicero, Suratt, & Inciardi, 2007; Rosenblum et al., 2007; SAMHSA, 2006).

In Europe, a transdermal formulation of buprenorphine has been approved for the treatment of chronic pain (e.g., Griessinger, Sittl, & Likar, 2005; Sittl, 2005). In post-marketing surveillance studies and in a multicenter randomized controlled clinical trial, the transdermal patches were reported to be effective and well-tolerated in the treatment of cancer and non-cancer chronic pain (Griessinger et al., 2005; Sittl, 2005; Sorge and Stittl, 2004; Sittl, Nuijten, & Nautru, 2006). A transdermal formulation of buprenorphine is not presently available in the United States.

The off-label use of sublingual buprenorphine tablets to treat chronic pain has been described in two clinical reports, one describing its use in a series of chronic pain patients who were responding poorly to other opioid analgesics (Malinoff et al., 2005) and the other describing the response of patients with both pain and addiction (Heit & Gourlay, 2008). In both of these reports, the authors reported that their patients were successfully treated with buprenorphine, e.g., pain relief and improved mood and functioning.

In a similar manner, two earlier publications describe the open-label use of the parenteral formulation of buprenorphine administered sublingually to treat patients with chronic pain (Adriaensen, Mattelaer, & Vanmeenen, 1985; Nasar, McLeavy, & Knox, 1986). Although most patients were followed up for less than one month, both studies reported good analgesia and low incidence or time-limited unwanted side effects. There is also evidence from several preclinical studies and one study with human subjects that, in contrast to pure mu-agonists, buprenorphine exerts a lasting anti-hyperalgesic effect (Hans, 2007; Koppert, et al., 2005). The transdermal trials conducted in Europe, the anecdotal reports of sublingual administration in North America, and buprenorphine’s comparatively high safety profile suggest that it would be valuable to systematically study buprenorphine as a treatment of pain in patients with substance use disorders.
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Conclusion

Opioids are among the most effective medications for moderate to severe pain. Although there is a consensus on their utility as a treatment for chronic cancer pain, their long-term use for chronic non-malignant pain remains controversial. Several medical professional organizations acknowledge the utility of opioid therapy and many case series and large surveys report satisfactory reductions in pain, improvement in function and minimal risk of addiction. However, the clinical trials that have been conducted do not provide adequate evidence of long-term effectiveness. Despite the consensus of pain specialists, and the eminently ethical and medically justified commentaries to consider opioid therapy in the armamentarium of treatments for moderate to severe pain (Brennan, Carr, & Cousins, 2007), there is concern that the pendulum has swung from undertreatment to overtreatment (White & Kehlen, 2007). This controversy is enhanced by the increased prevalence of prescription opioid abuse, which has developed concomitantly with an increase in opioid administration in the clinic. The resolution of this controversy will require much more research and the acceptance of treatment guidelines that recognize the dual obligations of the prescriber: to optimize the balance between analgesia and side effects, and promote other favorable outcomes, while concurrently assessing and managing the risks associated with abuse, addiction and diversion. At this juncture, it is important that the opioid treatment debate evolve from a discussion focused on “too little” or “too much” to one focused on identification and training of best treatment practices. Improvement in opioid therapy can occur through research and training to aid practitioners to determine the appropriate patient subpopulations and treatment protocols to achieve satisfactory outcomes.

Finally, it is imperative to advance a research agenda that leads to the identification of methods that would enhance pain relief while reducing the likelihood of addiction and other adverse events when opioids are selected for therapy. This should include the testing of novel medications that may be safer or more differentially effective for select treatment populations (as the proposal to test buprenorphine with high risk patients, discussed above) and the evaluation of treatment protocols incorporating risk management techniques.
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Acknowledgments

The authors wish to thank two anonymous reviewers who provided extremely thoughtful and helpful comments on an earlier version of this paper. Acknowledgement: Development of this paper was partially supported by a National Institute on Drug Abuse grant R21 DA022675.

References:

In order to find the references for this piece, you'll need to go to the original site - there are far too many to feature here (Ed.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711509/

How Drug Companies Need Their Patents

Today's post from burrillreport.com (see link below) is interesting because it shows us how drug companies are dependent on their patents for profits. In this case, the makers of Cymbalta (a common drug for the treatment of neuropathic symptoms), Ely Lilly have just lost their patent-exclusivity for Cymbalta and are therefore preparing for a big drop in revenue as other companies move in with alternatives to the drug. More competition is nearly always good news for the patient as it leads to greater choice and generally cheaper prices but there is another side to the story in that companies then have less revenue to invest in new research for newer drugs. It's how the pharmaceutical market works and considering their profit margins, we must be pleased when patents run out and alternatives become available. That said, neuropathy patients are still looking for the big breakthrough new drugs and that requires huge research funds, which are often generated by sales while current drugs are under patent. 

Eli Lilly Still Plans on Meeting 2014 Goals Company faces challenges, but is banking on new approvals and cost cutting.
DANIEL S. LEVINE The Burrill Report  October 03, 2013

“To reach its goals, Lilly says it is banking on targeted growth initiatives and the late-stage drugs in its pipeline.”

Eli Lilly told investors that despite the loss of revenue due to patent expirations for key drugs, it still plans on meeting its goals of generating at least $20 billion in revenue and $3 billion in profit for next year, returning to revenue growth and improving margins after that.

But to do so will be “challenging,” according to Lilly CFO Derica Rice, who noted that devaluation of the Yen and slower market growth in emerging market countries have diminished the company’s near-term expectations for sales growth. Rice says the company is finding appropriate ways to achieve its goals and will take additional actions to achieve its 2014 net income and operating cash flow targets through cutting expenses.

The comments came during a meeting with the investment community held at the company’s global headquarters in Indianapolis.

To reach its goals, Lilly says it is banking on targeted growth initiatives and the late-stage drugs in its pipeline. The company expects to launch several new drugs in 2014 with seven regulatory submissions for four different drugs made in 2013. This includes two drugs for type 2 diabetes and a drug for gastric cancer. The company also said it will make stock repurchases totaling $5 billion over time.

Lilly’s top-selling product, Cymbalta, for the treatment of major depressive disorder and general anxiety disorder, and pain associated with diabetic neuropathy, fibromyalgia and other chronic pain disorders lost patent exclusivity this year. Global sales of the drug accounted for roughly 25 percent of the company’s revenue in the last quarter, and generic selective serotonin and norepinephrine reuptake inhibitors on the market are predicted to reduce Lilly’s 2014 global revenue by 20 percent.

The company says its strategy to focus on development of innovative medicines has produced the strongest pipeline in its 137-year history, with 13 experimental drugs in late-stage clinical testing or in regulatory review and 26 more in mid-stage trials. That’s five times the number of candidates in mid-to-late-stage development than the company had in 2004.

“We’ve undertaken extensive efforts to transform our company to address the challenge of patent expirations and the demands of patients and payers for greater value from medicine,” says John Lechleiter, CEO of Lilly. “Today, we’re seeing our strategy bear fruit, backed by clinical data that strengthens our confidence in our innovation-based strategy and in our ability to return to growth.”

http://www.burrillreport.com/article-lilly_still_plans_on_meeting_2014_goals.html

We Need To Reduce Antibiotic Use And Misuse

Today's post from huffingtonpost.com (see link below) looks at antibiotics and explains why we've got to control their over-prescription, both because of growing resistance, the difficulty in developing new ones, and (in our case) the effect some of them can have on our nervous systems. There is no direct reference to neuropathy but it's a very important topic and certainly relevant to neuropathy sufferers if you look at the damages fluoroquinolone antibiotics can do to your nervous system (see more articles here on the blog). Worth a read.

Stop Killing the Good Guys! Protect Your Child's Microbiome From Antibiotic Overuse
Aviva Romm Practicing Family Physician, Midwife, Herbalist Posted: 01/08/2015

There's no doubt that antibiotics are a good thing. They save lives every day. We can, in part, attribute our longer lifespans, reduction in infant mortality and childhood deaths from life-threatening infections, and the near elimination of childbirth-related maternal deaths from infections in hospitals to antibiotics. As a medical doctor I am grateful to be able to prescribe them for serious bacterial and other appropriate infections, for example Lyme disease. As with many things, however, more is not always better. And this is certainly the case with antibiotics.

The average child in the United States will receive between and 10 and 20 courses of antibiotics by the time he or she is 18 years old. (2) We are so accustomed to antibiotics being prescribed for childhood illnesses that we assume that they are as safe as they are common. But this is far from the truth. We are now learning the hard way that the common overuse of antibiotics, both as medicines and in our foods (they are given to cattle and poultry to keep them "healthy" until they are slaughtered for food; antibiotics also promote growth in these animals by the same mechanisms that their chronic use increases the risk of obesity in humans) is responsible for two major health problems: global antibiotic resistance to serious infections, and damage to the human microbiome.

This growing awareness that antibiotic overuse is dangerous for both public and personal health requires us to drastically and immediately rethink and adjust our antibiotic use. In doing so we can prevent our children from developing life-long chronic illnesses associated with microbiome damage, some of which rival the seriousness of the bacterial infections that used to threaten them, and we can reduce the major global threat of antibiotic resistance we all face.

Antibiotics, Your Child's Microbiome, and Chronic Disease

Antibiotics kill bacteria. The problem is that they not only kill off the bad guys (and as you'll see below, because of antibiotic resistance, they are doing this less effectively!); they kill off the good ones, too. When we give antibiotics to children at a young age or frequently enough, some of the good guys may never fully recover. These good gut flora, and their composite, our microbiome, are essential for more functions that protect and support our health than we'd ever imagined until recently. We now know that microbiome damage directly and significantly increases the risks of our children developing long-term health problems including: food, environmental, and seasonal allergies, eczema, asthma, ulcerative colitis, Crohn's disease, obesity (even when they're not over-eating), diabetes, and cardiovascular disease. (1) (4)

Antibiotics are given to between 30 and 50 percent of all women during pregnancy or labor. (2) Mom's exposure to antibiotics perinatally also negatively affects the breast milk microbiome, which is part of what is supposed to help colonize baby's gut with beneficial flora. (5) Additionally, 34 percent of babies in the U.S. are born by cesarean. These babies miss out on the important inoculation their gut flora is meant to receive through natural exposure to mom's vaginal flora, thus compounding the problem. Our babies thus begin their antibiotic exposure even before birth, and as a result damage to their formative microbial populations begins before they've had a chance to establish their optimal gut flora. If your baby was born by cesarean section, or if you did need to have antibiotics in labor, no need to be worried! Start your baby on a probiotic in the day or so after birth. Data has shown that while we can't necessary restore the native flora baby might have had, we can prevent eczema, allergies, and asthma with early probiotic treatment. (6)

By age 24 months, 69 percent of children in the U.S. have received at least one systemic antibiotic course, though the average is 2.3 courses for ear infections, bronchitis, sore throat, and other common childhood illnesses. Yet according to the Centers for Disease Control, and other official reports, at least 50 percent and as many as 70 percent of the antibiotics prescribed for children for these and other symptoms/conditions are unnecessary and inappropriate. (3)

Reactions to antibiotics are responsible for at least 140,000 hospital visits annually in the US. (3) One in every five emergency department visits due to a medication reaction is due to antibiotics, and in kids under 18 years old they are the most common cause of drug reactions. When a child takes an antibiotic that is not needed, not only is she or he getting no benefit; she or he is exposed to all the risks of harm and the use of that medication adds to antibiotic resistance.Why are antibiotics overprescribed? There are four main reasons:
Doctors think that parents expect an antibiotic prescription when they bring their child in for a sick visit -- and many do -- leading to 50 to 70 percent of the antibiotics that are prescribed. (4)
Doctors are afraid to get sued should an infection that they didn't treat with an antibiotic turn out to be more serious than anticipated.
Doctors don't feel that they have time to explain the problems with antibiotics to parents in the time allocated for a child's sick visit, whereas it is quick and easy to prescribe an antibiotic.
Doctors aren't knowledgeable about alternatives to antibiotics and want to prescribe something they think will help.

The Centers for Disease Control and Prevention (CDC) has been on a several decade-long campaign to get physicians to reduce their antibiotic overprescribing. While there has been about a 20 percent decrease in antibiotic prescribing over the past 20 years as a result, the rates of overprescribing remain shockingly high, according to the CDC and other researchers. (3)

Antibiotic Resistance: A Global Health Threat

We are in the midst of a global health crisis -- antibiotic resistance, which is a direct result over the overprescribing and inappropriate prescribing of antibiotics, and the overuse of antibiotics in the meat industry.

Antibiotic resistance is not something that develops just in the individual -- that is, it's not just that you become resistant to that antibiotic -- it means that the bacteria themselves have learned to outwit the antibiotic so that the antibiotic is no longer effective in treating anyone who is infected with the resistant strain.

Each year in the U.S. alone over 2 million Americans acquire serious infections with bacteria that are now resistant to some or all of the antibiotics that we have to treat those organisms, and at least 23,000 people die each year as a result of antibiotic resistance. (3) Global leaders in public health have declared that these "nightmare bacteria" pose a catastrophic threat to every person in the world!

Five Steps to Preventing Antibiotic Overuse In Your Child
 
Promote health in your children: Preventing recurrent upper respiratory infections including coughs, colds, sore throats is an important and logical step you can take to prevent antibiotic overuse. Less need for them = less use of them! A healthy diet of natural foods with plenty of good quality protein, good quality fats, plenty of fresh vegetables, and low sugar, reduction of chronic stress, playing outside and getting dirty to get exposure to natural probiotics in the soil, and regular hand-washing with soap and water (don't use antibacterial soaps -- these also contribute to antibiotic resistance), along with a multivitamin that contains adequate iron, vitamin D, essential fats, and zinc, all support optimal immunity. The gut can also be nourished and the microflora supported with a probiotic.
Choose organic for your meats and dairy: While it may not be feasible for you to serve your family an entirely organic diet for economic reasons, at least use only antibiotic-free meats and poultry, and organic dairy. These are where the heavy antibiotic exposures come from in the diet -- so it's where you can make your money count most toward reducing antibiotic exposures.
Know your options -- Get Smart: The CDC has a website called Get Smart that is dedicated to preventing antibiotic resistance through preventing antibiotic overuse. You can find information on the primary infections for which antibiotics are overused, how to know when your child really does need an antibiotic, and how to avoid unnecessary use. Included is also information on comfort measures and medical alternatives for common symptoms ranging from cough and sore throat, to fever and ear infections. I don't necessarily agree with all of the CDC's alternative treatment recommendations, particularly the liberal use of Tylenol and ibuprofen, which have their own potentially serious side effects, but the overall information is very useful and also provides solid information to bring to your child's doctor's appointment to share with the pediatrician in case there is disagreement over whether the antibiotic is necessary and appropriate.
Know your rights: Doctors are not infallible nor are we omniscient. And not all doctors are aware of the importance of avoiding antibiotic overprescribing, so some may may insist on the prescription in spite of the CDC's guidelines. If you cannot reach agreement with your pediatrician, you have the right to seek another opinion or to change doctors. You should not be coerced into giving unnecessary antibiotics to your child. If your pediatrician is, however, insistent, find out why -- she may have a different perspective on your child's symptoms and of course the CDC guidelines are just that -- clinical judgment is also important.
Use natural treatments for the symptoms of common childhood illnesses whenever possible.

References
1. Bailey LC et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014 Sep 29
2. Blaser, M. Stop the killing of beneficial bacteria. Nature. Vol 476, 393-94. Aug. 2011.
3. CDC. Antibiotic Resistance Threats in the United States, 2013. US Dept of Health and Human Services, Centers for Disease Control and Prevention.
4. Dooling KL et al. Overprescribing and inappropriate antibiotic selection for children with pharyngitis in the United States, 1997-2010. JAMA Pediatr 2014 Sep 29
5. Williams, F. (2013). Breasts: A natural and unnatural history. New York: W.W. Norton.
6. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev. 2007;17: CD006475.

Aviva Romm, M.D. is a Yale-trained, Board Certified Family Physician, midwife, and herbalist helping extraordinary women live their best lives through optimal health. An award-winning author and the leading international authority on botanical, integrative and functional medicine for women and children, she combines her unique backgrounds to guide women in transforming their health -- and their lives. She is also a leader in the revolution to shift the current medical system into one that respects the healing capacities of the body and nature. Dr. Romm has bridged her interests in traditional medicine with her knowledge of science for over 30 years, specializing in the impact of stress, food and lifestyle on food cravings, weight, immunity, hormone imbalances, and women's chronic health concerns. She also provides comprehensive guidance on natural fertility, pregnancy, and birth, and pediatrics. Dr. Romm practices Functional Medicine for Women and Children at The UltraWellness Center with Dr. Mark Hyman in Lenox, MA. Visit her website www.avivaromm.com for free access to her e-book, Herbal Medicines for Kids: Taking Charge of Your Child's Health... Naturally.

http://www.huffingtonpost.com/aviva-romm/stop-killing-the-good-guy_b_6396546.html?utm_hp_ref=healthy-living