Dr. Panchal, an interventional pain physician who is president of the National Institute of Pain, discusses the challenges of treating patients with postherpetic neuralgia (PHN).
Sunil Panchal, MD
Dr. Sunil Panchal, an interventional pain physician who is president of the National Institute of Pain, discusses the challenges of treating patients with postherpetic neuralgia (PHN).
Can you give a brief overview of some of the risk factors and the pathophysiology of PHN?
After you’ve had chicken pox, the varicellazoster virus stays dormant inside the dorsal root ganglia. There are several factors that may contribute to the risk of it reactivating as shingles—an immunocompromised status, for example. Another major risk factor is age. There is a further risk of developing PHN that is also age-related. If you look at some of the data, you’ll see that patients above the age of 50 with shingles have a 50% greater chance of having the pain continue as a chronic neuropathic condition. The percentages go up for each decade. Primary care physicians need to be aware of the treatments that can help prevent shingles pain from developing into PHN. Many of them know to give antiviral medications to try to control the expression of the virus. But beyond that, a lot of them are not up to date on what they can do to prevent PHN. If the patient is expressing a significant intensity of pain, delayed treatment has a greater chance of causing neuropathic changes that can lead to a persistent pain state.
Studies that have shown that administering the tricyclic antidepressant (TCA) amitriptyline in addition to antiviral medications is associated with a 25% reduction in the incidence of developing PHN. Another study (http://1.usa.gov/JbHG1Z) showed that adjuvant injections of local anesthetic and steroids into the epidural space of patients who have shingles produce a significant reduction in the number of individuals who develop persistent pain.
If primary care physicians can treat with antivirals and amitriptyline or another TCA, and get the patient into the hands of an anesthesiologist or an interventional pain physician who can do epidural injections, they could drastically reduce the number of people with shingles who end up developing chronic, serious pain.
Are primary care physicians aware of these measures that can help prevent shingles from developing into PHN?
They’re pretty much unaware of it. Often, they’ll put the patient on antivirals and maybe prescribe a narcotic like Vicodin. If the patient still has persistent pain, then they’ll keep on prescribing different drugs, sometimes for as long as a year. But by then it’s too late for any procedural approach that could stop the development of PHN. A lot of patients end up with PHN unnecessarily. A significant number of patients could have this controlled more aggressively up front while the shingles are active.
"A lot of patients end up with PHN unnecessarily. A significant number of patients could have this controlled more aggressively up front while the shingles are active."
—Sunil Panchal, MD
Studies have shown that a large percentage of patients are unresponsive to PHN treatment. Why is PHN so hard to treat?
It depends on what tools you use, and what you limit yourself to. All patients are not the same mechanistically. You’ll have some patients with only partial nerve destruction; touching their skin where they had the rash aggravates it because there are still some nerves in that area that are sensitized. With PHN, you also have sensitization of nerves at the central level, at the spinal cord level. So some patients who have nerve damage that is so extensive that the nerves going to that part of the skin where they had the rash are completely destroyed will still complain of pain in that area, almost like a phantom pain. But when you touch the skin, it doesn’t aggravate their pain, because the processing of this neuropathic pain is all central now. And some patients have a mixed scenario—some of their pain is due to central neuropathic changes, and some of it is magnified by peripheral stimulation, because the nerve branch that’s going to the skin is still intact.
In patients who have some intact nerves to the skin, you can intervene with localized treatment. If you use a topical local anesthetic on this sensitized skin, you may be able to reduce their pain by blocking some of that nerve pathway. From the procedural side, you can try to modify that sensory input with electricity using nerve stimulators. In a few cases, we’ll knock out the intercostal nerve and ablate it to try to provide relief. If the pain is all central, then topical anesthetics are not going to work because there’s no nerve there that you can block. If it’s all centrally mediated, you’re going to be forced to rely on drug therapy, whether you continue the drugs orally or you’re putting the drugs directly into the spinal fluid.
With pain that is central, or mixed peripheral and central, we use antidepressant medications with the goal of trying to hit the alpha-2 receptor in the spinal cord to suppress nerve signaling. You’ll get a reasonable response (30-50% reduction in pain) in about 30-40% of patients using these drugs. Anticonvulsant drugs also control or suppress nerve signaling, whether you’re using a calcium channel-based drug or a sodium channel-based drug. That has also gotten reasonable results, with a 30- 50% reduction in pain in about 40% of individuals. Not everyone is going to respond to these medications. If you crank up the doses, some people may get some relief, but they might not be able to tolerate the side effects.
Is polypharmacy the name of the game?
There’s rational polypharmacy, and then there’s polypharmacy that’s more random. Often, patients will get started on an introductory dose of one of these drugs, but the clinician may not be aware of the full dose range, and not know that you have to push the dose up to a therapeutic level. So, the patient may be on an introductory dose for a month without obtaining any relief, but instead of thinking of it as a starting dose from which you titrate up, the clinician says “You failed this, so we’ll try another drug,” and they switch the patient from one drug to another. A lot of patients end up looking like “failures” because they never get titrated to a therapeutic level.
Does that speak to physicians’ lack of awareness of the medication options for effective treatment for PHN?
That’s a big part of it. There has been a lot of effort over the years to educate physicians about these dosing-related issues, especially now that some branded medications have a PHN indication. It’s a slow process to get physicians to change their habits. They don’t realize the different mechanisms might be additive. If you try one drug and you get a modest amount of relief, instead of stopping it and then switching to another drug, why don’t you try to combine complementary mechanisms? Rational polypharmacy is a logical approach, as long as you have an understanding of the mechanisms of how these medications work.
Then there’s the issue of trying to treat PHN with opioids. Neuropathic pain conditions typically are not very responsive to opioids unless you push the dose very, very high. But then you have to worry about side effects such as constipation, itching, nausea, hormonal changes, etc. Many primary care physicians are not aware that chronic opioid use can cause testosterone to drop, which can lead to osteoporosis. Some studies report there is a higher risk of spontaneous bone fracture in patients who take opioids. More recently there were studies reporting that cancer spreads more aggressively in the presence of opioids. Plus, if you ramp up the dose of opioids higher and higher you can end up with opioid-induced hyperalgesia. I don’t think awareness of this has percolated into the primary care environment.
In terms of treatment options, a once-daily formulation of gabapentin (Gralise) was recently approved. Are there any new PHN treatment options coming down the pipeline?
There are things that are in the early stage of the pipeline that may be effective for a variety of pain conditions, including PHN, but are not specifically targeted for PHN. The once-daily gabapentin medication that you mentioned offers an incremental benefit. Delivering the medication once a day improves compliance. If you’re giving it once a day at nighttime, the patient’s blood levels are going to be higher at night and not as high during the daytime, which addresses some of the concerns some people have about being sedated during the day when they’re on these centrally acting medications. Many of the patients who have tried this have only had previous experience with other existing anticonvulsants. I’m getting overwhelmingly positive responses from these individuals: they’re tolerating it better, they’re sleeping better, and they’re not feeling as drowsy or tired in the daytime.
It’s not going to give you a better quality relief than the prior existing formulation, but it definitely makes the side effects more tolerable.
How important is this to the overall quality of life for patients with PHN?
It’s very important in terms of getting patients to be compliant. Because anticonvulsants and antidepressants make people drowsy or tired, we don’t start them at a therapeutic dose. We start them at a low dose, and then we gradually titrate the dose up. If patients can’t tolerate it, they don’t stay on the regimen, even if it could potentially provide them some relief. For this once-daily formulation, because you know the tolerability is greater, you have a better chance of finding out if the patient actually responds to this medication, as opposed to quitting before they even get to a therapeutic dose. I think it’s an important benefit.
What about other treatment options?
For severe cases of PHN, if the patient is failing oral systemic route therapy, if they’re being limited by side effects, or if they want to avoid opioids, then primary care physicians should be familiar with spinal pump therapy, which delivers small amounts of medication directly into the spinal fluid and reduces side effects.
There are non-opioid medications that can be given with a spinal pump. There’s an FDA-approved calcium channel blocker, ziconotide (Prialt), which hits an end-type calcium channel that only sits on the pain pathway. Off label, we’ll combine a local anesthetic with the pump medication, or the blood pressure medication clonidine, which hits the alpha-2 receptor in the spinal cord and has an inhibitory effect on pain transmission.
One rationale for using spinal pumps is to get better results in patients on opioid therapy that are limited by side effects and want to reduce how much opioid they’re getting. Another is for patients who don’t want to be on opioid therapy at all and have tried other options like nerve stimulation with limited results. For them, ziconotide infused in minute quantities is an option. If that gives them adequate relief, then you’re meeting the patient’s goals. It’s about understanding what the patient’s goals are and then trying to find a match with the available therapies that can help achieve them.