Tackling Nerve Pain

Motivation: Pain is the bane of internists - particularly neuropathic pain. The gnawing, burning pain keeps people (patients and internists) up all night debating whether to use IV opioids.  And, gabapentin hardly seems up to the job.  There were several instances last year when even mega-doses of gabapentin failed to lessen the pain.  I often wondered at that point, what next?  To start a new agent, should I stop gabapentin? (And, is this pain real?)

During a clinic this year, one of the attendings pointed out a helpful trial that attempted to deal with failed control of neuropathic pain.  The trial tested combination of tricylcic agent nortriptyline with gabapentin.  As way of background, gabapentin is an alkylated analogue of GABA that is actually thought to work through modulating calcium channel subunits.  Nortriptyline is derived from amitriptyline with multiple effects including blockade of norepinephrine and serotonin re-uptake, blockade of sodium channels, anti-cholinergic actions, and antagonism of NMDA receptors.

Paper: Gilron, I., Bailey, J.M., Tu, D. et. al. "Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial" Lancet (2009); 374: 1252.

Methods: Double-blind crossover trial in patients with diabetic polyneuropathy and postherpetic neuralgia with persistent neuropathic pain. Randomized trial of three treatments - gabapentin, nortriptyline, and combined gabapentin and nortriptyline.  In crossover design, each of three groups spent 6 weeks in each of the three treatment groups (received placebo pill for second agent when getting just gabapentin or nortriptyline).  After 6 weeks, each of the groups were switched to one of the other three treatment assignements.  During the trial period, drug doses were titrated to maximum tolerated dose.  Primary outcome was mean daily pain (0-10 rating scale).

Results:
Subjects: The trial enrolled total of 56 participants.  Of these patients, 40 had diabetic polyneuropathy and 16 had post-herpetic neuralgia.  All of the patients were white with men comprising 65% of diabetic groups and 56% of post-herpetic neuralgia group.  In the diabetic group, 20% were taking opioids with about 33% having been exposed to prior tricyclic and 20% having been exposed to gabapentin/pregabalin.  Similarly, in the post-herpetic neuralgia group, 25% were taking opioids with about 31% having been exposed to prior tricyclic and 44% having been exposed to gabapentin/pregabalin.

Gabapentin vs. Nortriptyline: As monotherapy, both gabapentin and nortriptyline achieved lower daily pain intensity compared to baseline (5.4 in baseline vs. 3.2 for gabapentin; 5.4 vs. 2.9 for nortriptyline). The pain rating is significantly lower from baseline but is not significantly different between drugs.  Similarly, neither drug was superior to each other in terms of worst pain in 24 hours, least pain in 24 hours, or percentage pain relief on treatment.

Combination Therapy: Combined nortriptyline and gabapentin was significantly superior to gabapentin and nortriptyline monotherapy in terms of daily pain intensity (2.3 in combination vs 3.2 for gabapentin alone, p=0.001; 2.3 vs 2.9 for nortriptyline, p=0.02).  Combination therapy also provided better percentage pain relief on treatment (63.4% vs. 48.1% for gabapentin, p=0.007; vs. 45.7% for nortriptyline, p=0.002).  In secondary analysis, Beck depression score was significantly better for combination therapy compared to nortriptyline (5.4 vs. 6.8 for nortriptyline, p=0.01).  Self-reprorted vitality was also higher with gabapentin and combination therapy compared to nortriptyline alone. Depression scores were not different between combination therapy and gabapentin.

Dosage: As monotherapy, average maximum doses of gabapentin was 2433 mg/day while that of nortriptyline was 61.6 mg/day.  In combination, average gabapentin dose was 2180 mg/day and nortriptyline dose was 50.1 mg/day.

Adverse Effects: No serious side effects were noted.  Dry mouth was more frequent with nortriptyline while inability to concentrate was more frequent with gabapentin.

Discussion: For patients with poorly controlled neuropathic pain, combination therapy with nortriptyline and gabapentin was superior to monotherapy.  While both drugs appeared to be equivalent in terms of controlling pain, I was surprised at the worse depression scores and decreased vitality with nortriptyline monotherapy compared to gabapentin.  Given the alternate use as anti-depressant, I would have expected nortriptyline to be at least as good as gabapentin in terms of mood.  This analysis is, of course, secondary and limited by the small number of subjects (56 total patients), but given the limited data, I would start with gabapentin monotherapy and then add nortriptyline as an adjunctive agent.  Another cautionary note is that the tolerated doses of gabapentin in the trial was more than 2000 mg/day.  With the usual starting dose of 300 mg thrice daily, the drug needs to be significantly uptitrated prior to pronouncing therapeutic failure.

Preserve your wisdom

Motivation: I dislike going to the dentist.  I do not mind the whining drill, but after finishing poking through my teeth, every dentist tells me to take out all my wisdom teeth.  And, I have resisted for more than a decade.  In few other fields of medicine are prophylactic painful procedures so prevalent for a less than life-threatening outcome - a cavity in a wisdom tooth.  To further solidify my argument for my next visit, I wondered about the data backing this recommendation.

As way of background on dentistry, current American guidelines recommend extracting wisdom teeth that fail to erupt completely ("impacted wisdom teeth" in dentistry parlance) preferably during adolescence.  Since no randomized trials exist in adults, reviewed below is a paper which examines the strength of existing evidence.

Paper:  Shallu, B. and Rajesh, S. "Is it Wisdom to Remove a Wisdom Tooth? - Extraction versus nonextraction Management of Impacted Tooth" Ind. J. of Den. Sci. (2010); 2: 4-6

Results:
Incidence of Pathology in Wisdom Teeth: When followed for four years, about 10% of non-erupted wisdom teeth result in adults develop surrounding gingival inflammation or pericoronitis.  There is low incidence (less than 1%) of root resorption in surrounding molar teeth as a result of non-erupted wisdom teeth.  Incidence of inflammation spreading from wisdom teeth to surrounding teeth (ie. causing dental caries) is estimated at 1 to 4.5%.

Early Removal of Wisdom Teeth vs. Later Removal: In post-intervention series, persons aged 35 to 83 years of age were less likely to experience dry socket, secondary infection, and parasthesias compared to those aged 12-24.  The highest risk of complications occurred in people aged 25 to 34 years.

Erupting Wisdom Teeth Causing Crowding of Anterior Teeth: Primarily theoretical prediction without substantial longitudinal clinical data.  (From a Cochrane review), a single trial comparing outcomes at 5 years did not find substantial differences between tooth extraction and observation.

Discussion: I think that I will take the one out of ten chance that keeping wisdom teeth may result in pathology in the next four years.  There are no data to support benefits of early asymptomatic extraction.  In fact, in England, the governmental health organization, NICE, recommended against prophylactic removal of asymptomatic wisdom teeth.  A similar Cochrane review on this topic also found insufficient evidence.  I was personally surprised at the lack of data given the estimated mutli-billion dollar industry among oral surgeons dedicated to wisdom tooth removal.  I think that like other similar problems in medicine such as with gallstones, preventive intervention may not be justified on a population basis. 

Is High Fructose Corn Syrup Unhealthy?

Motivation: Somehow we all know it - high fructose corn syrup makes you gain weight. I cannot remember when I first heard it or when I last read something about it, but this notion is spreading from the health community outwards.  I even had a patient ask me about avoiding foods with high fructose corn syrup.  Not knowing much beyond rumors, I felt that it was time to investigate the merits of different kinds of sugars.  What is the data linking high fructose corn syrup to the epidemic of obesity and diabetes?

As way of background, regular sugar consists of sucrose, which is a disaccharide of fructose and glucose.  High fructose corn syrup (HFCS), in contrast, consists of monosaccharides with varying concentrations of fructose and glucose (from 42% to 90% fructose).

Paper: Forshee, R.A., Storey, M.L., Allison, D.B. et. al. "A Critical Examination of the Evidence Relating High Fructose Corn Syrup and Weight Gain" Crit. Rev. in Food Sci. and Nut. (2007); 47:561-582.

Method: Systematic review conducted by expert panel convened by Center for Food, Nutrition, and Agriculture Policy to examine the evidence linking HFCS and changes in BMI/body weight.

Results:
The strength of evidence from different classes of evidence are summarized below. Given the breadth of evidence, only significant studies are presented:

Ecological Studies: These are large scale studies linking trends between food consumption and health measures.  Between 1909 to 1997, incidence of type 2 diabetes was positively and significantly correlated with corn syrup intake along with intake of fat, total carbohydrate, protein, and total energy.  Using food-consumption data to estimate sweetener consumption from 1962 to 2000, the authors found a 74 kcal/person increase in per capita sweeter availability in this time period.  No causality with disease is implicated in this study.

Cross-Sectional Studies: Four studies were identified examining relationship between soft or sweetened drink consumption (proxy for HFCS) and obesity.  Three out of four studies found that sweetened regular soft drinks were not significantly associated with BMI. One study among European American children showed positive association between overweight and sweetened beverages along with association with consumption of increased total food and beverages.

Longitudinal Studies: Four studies examined growing children and sweetened drink consumption.  Three out of these four studies did not find any association in excess of total calories consumed.  One study showed that over 19 months, BMI increased by 0.24 units for every additional serving of sweetened drink.

Among adults, when 38,480 women health professionals were followed, total caloric sweetener (fructose or glucose) consumption did not correlate to risk of type 2 diabetes.  Another study also examined sweetened beverage consumption among women 24-44 for 15 years and did not find excess weight gain among high consumers of sweetened beverages.  The study did find that women who moved from low consumption to high consumption were at higher risk of weight gain.

Controlled Trial: Only one RCT has been performed to test this question among children 7-11 years of age.  The intervention group received education emphasizing healthy diet and discouraged sweetened and carbonated beverages.  Mean percentage of overweight and obese children decreased in the intervention arm.

Discussion: In summary, the evidence linking high fructose corn syrup and obesity is circumstantial at best.  The overall upward trend in obesity and diabetes can also be explained by increased caloric intake - which has paralleled the weight gain the past few decades.  Of course, the evidence also does not conclusively refute the hypothesis that HFCS is in part responsible for accelerating obesity.  Given the complex interactions between food habits and general health habits, it is hard to see how anything besides a randomized trial can provide more definitive evidence.  For now, though, to avoid obesity and diabetes, limiting caloric intake is likely a better idea than avoiding high fructose corn syrup.