How Vitamin B12 Helps To Reduce Or Prevent Nerve Pain

Today's interesting post from liveitholistic.com (see link below) looks in detail at vitamin B12 and the role it plays in helping with and preventing neuropathy. Many people take vitamin B12 supplements for nerve pain because they've heard or read that it helps but few know why they do. Most neurologists will agree that a vitamin B (and B12 in particular) deficiency can cause nerve damage but it's rare that you see a breakdown of how vitamin B actually works in the body. This is such an article and therefore an important one for neuropathy patients. Well worth a read.

The Importance of B12 and its role in Neuropathy and Anemia. 
Marc Capistrano June 19, 2016
 
The stars have aligned on this post. The topic of B12 keeps coming up lately, and it was a sign that I had to put something up on the blog. The thing about writing is that it’s almost like a personal journal (…here’s what’s on my mind at this point in time and how I feel about it.)

In this case, Vitamin B12 is on my mind!

It’s involved in every metabolic cellular process in our body, DNA production and nerve function to name a few.

A good balance of all b-vitamins is important but B12 tends to get most of the attention because it is not absorbed into the blood stream the same way the other b’s are. B12 is usually more deficient than the other b-vitamins due to a deficiency in Intrinsic Factor. It also binds with “intrinsic factor” (It’s a specialized type of protein produced in the stomach). B12 must be bound to Intrinsic Factor. Then it is absorbed in to the small intestine (There are receptor sites for B12). You need to produce HCL in order to produce intrinsic factor. You also need to produce enough HCL to produce pepsin. Intrinsic (IF) is internally produced. On the other hand, B12 is the extrinsic (outside) factor produced.

Ok Marc. Tell me why B12 vitamins are important.

1. It prevents Peripheral Neuropathy: The myelin sheath acts as an insulating cover over a nerve fiber. It’s through this nerve fiber that conduction impulses are produced and electrical signals are sent and received. Think of it this way, you touch something hot, once the sensation is felt, your nerves send a signal to your brain. This signal works on these conduction impulses. If you don’t know, now you know ***Biggie Voice***.

Well B12 prevents the breakdown of the myelin sheath that covers our nerve fibers (also known as “demyelination”). When we hear myelin sheath, we usually associate this with the brain (MS). But, the myelin is also very important for your spinal cord’s nerve fibers. This damage leads to a condition known as peripheral neuropathy, in which symptoms include loss of coordination, sensory touch and eventual decreased muscle mass.

It’s shown that B12 intake from food and supplementation can improve neuropathy conditions. With issues like tingling, muscular dysfunction and especially neuropathy, it’s best to have a specialist (Chiropractor, Physiotherapist) look at you and make a proper diagnosis. As a nutritional practitioner, my job is to support the physical intervention through nutrition once a person is diagnosed.

2. The effects of B12 deficiency can cause irreversible symptoms: This is seen in Multiple Sclerosis (a degenerative disease of the nervous system). As with any tissue in the body, once it’s damaged, scar tissue forms (also known as Sclerosis).

3. A lack of B12 can lead to Pernicious Anemia: This is a form of anemia caused by a lack of absorption of B12 due to a deficiency in Intrinsic Factor. B12 binds with “intrinsic factor” as I had mentioned earlier. Without B12 and Intrinsic factor, the membranes of immature red blood cells rupture, disintegration of the stomach lining can occur which can lead to autoimmune diseases such as Crohn’s disease.

4. It makes us happy: B12 plays an important role in supporting and assisting with the formation of neurotransmitters such as serotonin and dopamine production. And this, make us happy…

5. B12 helps us recycle Homocysteine: Anyone out there with a history of cardiovascular disease will have some knowledge of homocysteine levels. If you don’t, then just know that homocysteine is created as a by-product of our body’s metabolism of methionine and cysteine.

Homocysteine isn’t all bad, it still gives us things like Cysteine, which is a precursor to glutathione (an amino acid known for its detoxification capabilities) and is important to the synthesis of Neurotransmitters. The only problem is that high levels of homocysteine are indicative of cardiovascular and neurodegenerative diseases. B12 is important in taking homocysteine and converting it back to methionine.

Ok…What do I do?

Before we get into the details of B12 intake, it’s important to note that all b vitamins including B12 are depleted in the body by things like stress, birth control pills and high intake of sugars.

1. Some people can’t produce Intrinsic Factor. If this is the case, B12 shots are available. You’ll want to buy Methylcobalamin (the active form), not Cyanocobalamin.

2. HCL (stomach acid) is required in order to take B12 from its protein carrier Intrinsic Factor. Refrain from antacids and supplement with Hydrochloric acid with betaine to improve stomach pH.

3. If you’re simply deficient and looking for the next best thing to a shot, then a sublingual (under the tongue) is another alternative option. This skips the digestion process and gets right into the bloodstream. People looking to simply optimize or increase B12 intake can take a Vitamin B complex with a higher B12 content.

4. B12 food sources: Liver, Meat Protein, Dairy, and Seafood (particularly shellfish).

5. The liver has to activate B-vitamins. If you have an under functioning liver, then B-vitamins are not being absorbed. Support the liver, and the b-vitamins will follow!

6. Supplements and B12 aside, it’s important to look at the root cause of demyelination (breakdown of the nerve fiber). In some cases, autoimmune conditions cause the self-destruction of the myelin sheath. Eliminating triggers that cause chronic inflammation (high sugar, poor diet etc.…) can prove to be your best prevention and early treatment. The entry of pathogens through the blood brain barrier affects the CNS, which in turn affects the peripheral system. Boosting your immune system can also be a great way to properly limit the amount of sclerotic tissue that forms.

http://www.liveitholistic.com/blog/2016/6/19/the-importance-of-vitamin-b12-and-its-role-in-neuropathy

BIOCHEMISTS SOLVE ADDRESS PROBLEM IN CELLS THAT LEADS TO LETHAL KIDNEY DISEASE

Research by UCLA biochemists may lead to a new treatment -- or even a cure -- for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson's disease, Alzheimer's disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme -- called alanine: glyoxylate aminotransferase, or AGT -- goes to the proper "address" in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal's print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria -- tiny power generators in cells that burn food and produce most of the cells' energy -- which causes PH1.

Koehler's team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

"In many mutations that cause diseases, the enzyme doesn't work," Koehler said. "In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria 'mailbox' and takes it to the peroxisome address instead."

How often did it work?

"All the time," said Koehler, a member of UCLA's Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar "correct address" strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson's, Alzheimer's and other diseases.

PH1 -- short for primary hyperoxaluria 1 -- starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists' ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

"It's exciting that our studies in baker's yeast, a typical laboratory model, might be able to help kids with a complicated disease," Koehler said.

ANTIBIOTICS GIVE RISE TO NEW COMMUNITIES OF HARMFUL BACTERIA

Most people have taken an antibiotic to treat a bacterial infection. Now researchers from the University of North Carolina at Chapel Hill and the University of San Diego, La Jolla, reveal that the way we often think about antibiotics -- as straightforward killing machines -- needs to be revised.

 The work, led by Elizabeth Shank, an assistant professor of biology in the UNC-Chapel Hill College of Arts and Sciences as well as microbiology and immunology in the UNC-Chapel Hill School of Medicine, and Rachel Bleich, a graduate student in the UNC-Chapel Hill Eshelman School of Pharmacy, not only adds a new dimension to how we treat infections, but also might change our understanding of why bacteria produce antibiotics in the first place.

"For a long time we've thought that bacteria make antibiotics for the same reasons that we love them -- because they kill other bacteria," said Shank, whose work appears in the February 23 Early Edition of the Proceedings of the National Academy of Sciences. "However, we've also known that antibiotics can sometimes have pesky side-effects, like stimulating biofilm formation."

Shank and her team now show that this side-effect -- the production of biofilms -- is not a side-effect after all, suggesting that bacteria may have evolved to produce antibiotics in order to produce biofilms and not only for their killing abilities.

Biofilms are communities of bacteria that form on surfaces, a phenomenon dentists usually refer to as plaque. Biofilms are everywhere. In many cases, biofilms can be beneficial, such as when they protect plant roots from pathogens. But they can also harm, for instance when they form on medical catheters or feeding tubes in patients, causing disease.

"It was never that surprising that many bacteria form biofilms in response to antibiotics: it helps them survive an attack. But it's always been thought that this was a general stress response, a kind of non-specific side-effect of antibiotics. Our findings indicate that this isn't true. We've discovered an antibiotic that very specifically activates biofilm formation, and does so in a way that has nothing to do with its ability to kill."

Shank and her team previously reported that the soil bacterium Bacillus cereus could stimulate the bacterium Bacillus subtilis to form a biofilm in response to an unknown secreted signal. B. subtilis is found in soil and the gastrointestinal tract of humans.

Using imaging mass spectrometry, they subsequently identified the signaling compound that induced biofilm production as thiocillin, a member of a class of antibiotics called thiazolyl peptide antibiotics, which are produced by a range of bacteria.

At that point, Shank and her colleagues knew thiocillin had two very specific and different functions, but they didn't know why -- and wanted to know how it worked. That's when they modified thiocillin's structure in a way that eliminated thiocillin's antibiotic activity, but did not halt biofilm production.

"That suggests that antibiotics can independently and simultaneously induce potentially dangerous biofilm formation in other bacteria and that these activities may be acting through specific signaling pathways," said Shank. "It has generated further discussion about the evolution of antibiotic activity, and the fact that some antibiotics being used therapeutically may induce biofilm formation in a strong and specific way, which has broad implications for human health."

CELL DEATH PROTEINS KEY TO FIGHTINING DISEASE

Melbourne researchers have uncovered key steps involved in programmed cell death, offering new targets for the treatment of diseases including lupus, cancers and neurodegenerative diseases

The research teams from the Walter and Eliza Hall Institute worked together to discover the three-dimensional structure of a key cell death protein called Bak and reveal the first steps in how it causes cell death. Their studies were published in Molecular Celland Proceedings of the National Academy of Sciences.

Programmed cell death, known as apoptosis, occurs naturally when the body has to remove unwanted cells. Chemical signals tell the cell to die by activating the apoptosis proteins Bak and Bax, which break down the 'energy factory' of the cell, known as the mitochondria. When this process goes awry, defective cells such as cancer cells can continue to live, or healthy cells can die unnecessarily, such as occurs in Alzheimer's disease.

Visualizing death proteins

Using the Australian Synchrotron, Mr Jason Brouwer, Dr Peter Czabotar, Dr Ruth Kluck and colleagues from the institute's Structural Biology division investigated how the structure of Bak changes in order to initiate cell death. The research was published in Molecular Cell.

"Understanding the way cell death proteins work and what they look like is crucial to finding new ways to treat disease," Dr Czabotar said. "Our research showed how Bak morphs from one shape to another to trigger apoptosis. Once Bak becomes 'activated' within the cell, it couples with another Bak molecule to form a 'dimer', which then goes on to initiate apoptosis."

Dr Czabotar said understanding apoptosis would allow researchers to develop new ways to treat disease. "Knowing the structure of these proteins and how they work in the cell is essential in designing new treatments to fight disease."

Seeking the hole story

Dr Dana Westphal, Dr Kluck, Dr Grant Dewson, Professor Jerry Adams and colleagues from the Molecular Genetics of Cancer and Cell Signalling and Cell Death divisions examined how the Bak and Bax dimers attach to mitochondria and perforate them. The research was published in Proceedings of the National Academy of Sciences.

Dr Kluck said dimers of Bak and Bax break open the mitochondrial surface, but the mechanism remains poorly understood. "A crucial stage of apoptosis is the release of key proteins from within the mitochondria," she said. "Scientists thought this happened by Bak and Bax poking through the mitochondrial membrane to form a hole, but our work has shown this doesn't happen. Instead, these proteins collapse onto the oily surface of the mitochondria and crowd the surface until holes form."

"We and others are now working to discover exactly how these proteins come together to destroy the mitochondria and trigger apoptosis. A deeper understanding of this pivotal event is likely to suggest new ways to regulate apoptosis to combat disease."

 

POOR SPERM QUALITY LINKED TO HYPERTENSION OTHER HEALTH PROBLEMS

A study of men who were evaluated for the cause of their infertility finds previously unknown relationships between deficiencies in their semen and other, seemingly unrelated health problems.

A study of more than 9,000 men with fertility problems has revealed a correlation between the number of different defects in a man's semen and the likelihood that the man has other health problems.

The study, conducted by investigators at the Stanford University School of Medicine, also links poor semen quality to a higher chance of having various specific health conditions, such as hypertension, and more generally to skin and endocrine disorders.

The findings, published online Dec. 10 in Fertility and Sterility, may spur more-comprehensive approaches to treating male infertility. They also point to the wisdom of performing complete physical examinations of men experiencing reproductive difficulties.

"About 15 percent of all couples have fertility issues, and in half of those cases the male partner has semen deficiencies," said the study's lead author, Michael Eisenberg, MD, assistant professor of urology and director of male reproductive medicine and surgery at Stanford. "We should be paying more attention to these millions of men. Infertility is a warning: Problems with reproduction may mean problems with overall health."

A study Eisenberg co-authored a few years ago showed that infertile men had higher rates of overall mortality, as well as mortality linked to heart problems, in the years following an infertility evaluation. "But here, we're already spotting signs of trouble in young men in their 30s," he said.

Analyzing medical records

In the new study, Eisenberg and his colleagues analyzed the medical records of 9,387 men, mostly between 30 and 50 years old, who had been evaluated at Stanford Hospital & Clinics (now Stanford Health Care) between 1994 and 2011 to determine the cause of their infertility. The men had routinely provided semen samples, which the researchers assessed for characteristics including volume, concentration and motility. In about half of all the male infertility cases, the problem was abnormal semen; in the rest, the fault lay elsewhere. So, using the database, the investigators were able to compare the overall health status of men who had semen defects to that of the men who didn't.

With a median age of 38, this was a fairly young group of men. However, 44 percent of all the men had some additional health problem besides the fertility problem that brought them to the clinic. In particular, the investigators found a substantial link between poor semen quality and specific diseases of the circulatory system, notably hypertension, vascular disease and heart disease. "To the best of my knowledge, there's never been a study showing this association before," said Eisenberg. "There are a lot of men who have hypertension, so understanding that correlation is of huge interest to us."

In addition, as the number of different kinds of defects in a man's semen rose, so did his likelihood of having a skin disease or endocrine disorder. When looking at the severity of all health problems, the scientists observed a statistically significant connection between the number of different ways in which a man's semen was deficient and the likelihood of his having a substantial health problem.

Health, semen quality 'strongly correlated'

The study wasn't designed to determine precisely how connections between semen deficiencies and seemingly unrelated disorders, such as cardiovascular or endocrine disease, come about. But, Eisenberg noted, some 15 percent of all genes in the human genome are connected fairly directly to reproduction, and most of these genes also have diverse functions in other bodily systems. He also noted that it may not be a disease itself, but the treatment for the disease, that's actually responsible for reproductive malfunction. He said he is exploring this possibility now.

As we treat men's infertility, we should also assess their overall health.

"A man's health is strongly correlated with his semen quality," he said. "Given the high incidence of infertility, we need to take a broader view. As we treat men's infertility, we should also assess their overall health. That visit to a fertility clinic represents a big opportunity to improve their treatment for other conditions, which we now suspect could actually help resolve the infertility they came in for in the first place."

The senior author of the study is Mark Cullen, MD, professor of medicine at Stanford. Other Stanford co-authors are professor of reproductive endocrinology and fertility Barry Behr, PhD; former professor of obstetrics and gynecology Renee Reijo Pera, PhD; and statistical programmer Shufeng Li.

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New Ways To Repair Nerve Pathways

Today's post from (see link below) looks at new discoveries about dendrites, which are a component of nerve cells which receive information from the brain. It explains that these dendrites are capable of rapid re-growth after injury. before it was thought that axons (part of the cell which sends information to other cells) were the only cell components capable of regeneration. Discovering that dendrites can do it even more quickly and independently of axons may lead to treatments which can promote this activity and thus repair nerve damage more effectively. Sure, all this investigation has been done via fruit flies but the science always has to be established first before it can be applied to human injury - fascinating.

New Pathway for Neuron Repair Discovered  
Jan. 9, 2014 Story Source: The above story is based on materials provided by Penn State.

— Penn State University molecular biologists have discovered a brand-new pathway for repairing nerve cells that could have implications for faster and improved healing. The researchers describe their findings in a paper titled "Dendrite injury triggers DLK-independent regeneration," which will be published in the 30 January 2014 issue of the journal Cell Reports. These findings demonstrate that dendrites, the component of nerve cells that receive information from the brain, have the capacity to regrow after an injury.

Previous studies using many models have shown that when nerve cells, or neurons, are injured they repair the damage through regrowth of axons, the component of a neuron that sends information to other cells, explained co-author Melissa Rolls, associate professor of biochemistry and molecular biology at Penn State. "For example, if you break your arm and the bone slices some axons, you may lose feeling or movement in part of your hand. Over time you get this feeling back as the axon regenerates."

Using the fruit fly (Drosophila) as a model system, the researchers took what Rolls calls a "radical approach," cutting off all of the dendrites in neuron cells. "We wanted to really push the cells to the furthest limit," she said. "By cutting off all the dendrites, the cells would no longer be able to receive information, and we expected they might die. We were amazed to find that the cells don't die. Instead, they regrow the dendrites completely and much more quickly than they regrow axons. Within a few hours they'll start regrowing dendrites, and after a couple of days they have almost their entire arbor. It's very exciting -- these cells are extremely robust."

Moreover, it appears that dendrite regeneration happens independently of axon regeneration. When Rolls and her colleagues blocked the key signaling molecules that are required for axon regeneration in all animals, they found that dendrites were unaffected and continued to regrow. "This means that, not only do these neurons have an incredible ability to generate, they have two different regeneration pathways: one for axons and one for dendrites," she said. "Because it has not even been clear that dendrites can regenerate, it's a complete open question about what might be involved in that process. The next step will be to look for markers for dendrite regrowth -- proteins that are required or genes that are turned on in the process -- so we can learn more about what's going on during dendrite repair. We don't even know in what scenarios dendrite regeneration might happen in people yet because no one has known that it exists."

The implications for human health -- although a long way down the road -- are important, Rolls said. For example, in the case of stroke, when a region of the brain suffers blood loss, dendrites on brain cells are damaged and can be repaired only if blood loss is very brief. Otherwise, it is thought those brain cells die. But if those cells are able to regenerate dendrites, and if scientists learn how dendrite regrowth happens, researchers may be able to promote this process.

"We've provided some cause for hope when it comes to neuron damage," Rolls said. "This is optimistic work we are doing. It's just great to know there is this whole other pathway for survival that no one has even looked into before."

 http://www.sciencedaily.com/releases/2014/01/140109132422.htm

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.

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