Immune activation and autoimmunity in chronic pain conditions and response to immunoglobulin G

The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant, sensory and emotional experience associated with actual or potential tissue damage, or described in such terms’ 1. Pain has the evolutionary function of alerting us to tissue damage, so that we are generally unable to ignore it. Sensory aspects of a pain experience (where it is felt) and emotional aspects (how it is perceived) are simultaneously activated by peripheral noxious trauma, but are dealt with in completely separate areas of the brain.

Of the general population, 15–20% 2 are affected by chronic pain. Chronic pain disorders can be defined as conditions for which pain is the primary symptom of concern. These conditions are difficult to treat; even the strongest pain relief medications for acute pain, such as intravenous opioids, often have little beneficial effect in chronic pain. In recent years, scientists have begun to define an important role for peripheral and central immune mechanisms in sustaining chronic pain. Chronic pain conditions are rarely associated with structural abnormalities, and systemic inflammatory markers are usually normal. It is thought that peripheral immune activation often occurs in non-neuronal tissues. For example, in patients with irritable bowel syndrome (IBS), it appears that mast cells in the mucosal surfaces are situated closer to sensory nerve endings than in people without IBS, and there is an inverse correlation between the average nerve–mast cell distance and the degree of pain.

Some chronic pain conditions, such as complex regional pain syndrome (CRPS), are post-traumatic. In experimental models of post-traumatic chronic pain, in addition to peripheral immune activation, central immune activation is generally also observed. There is evidence showing that the degree or presence of such central immune activation is associated with the development of chronic pain. Blocking the central immune response using drugs can be sufficient to interrupt chronic pain.

In addition to these subtle immune activations, which have been observed in a number of different pain conditions, we have demonstrated the presence of autoantibodies in CPRS which we believe may contribute to the CRPS pain; this could also be the case for other chronic pain conditions. It is hypothesized that, following injury or trauma, the natural inflammatory response at the site of trauma facilitates the pathogenic activity of pre-existing autoantibodies through as yet unknown mechanisms. The autoantibodies may be present for only a limited time at a sufficiently high concentration to help trigger the pain disorder. Trauma which occurs during a ‘window of vulnerability’ may trigger autoantibody activity and chronic pain 3,4.

Subtle, immune-elicited, peripheral sensory nerve activation (e.g. through mast-cell mediators or autoantibodies) is unlikely to be painful in itself; the cause of the chronic pain is instead understood most clearly within the conceptual framework of ‘central sensitization’ (Fig. 1).

Figure 1.

Central sensitization. The normal pain response is shown by the blue curve; in chronic pain conditions, the pain response (shown by the red curve) is heightened and the curve shifts to the left. This means that otherwise painless, or less painful, stimuli can now cause a pain response, known as allodynia and hyperalgesia (reproduced from 9,copyright 2001, with kind permission from David Klemm).

In a healthy individual, a slight amount of pressure or heat on the skin is not painful; when this is gradually increased, the pain response moves up the blue curve. If the pressure or heat continued to increase, everyone would eventually feel pain. Due to central sensitization, the pain response of patients with chronic pain follows the red curve, meaning that a very slight stimulus will cause pain. This is known as allodynia, and can be visualized by the area on the graph which on the blue curve would indicate no pain, but on the red curve would indicate a pain response. Independently, at the point on the blue line where a normal person would feel pain, on the red line the pain levels are much higher for a person with central sensitization; this phenomenon is known as hyperalgesia.

The mechanisms of some chronic pain conditions, such as phantom limb pain are largely centred in the brain, and these mechanisms are sometimes subsumized under ‘central sensitisation’. In contrast, the type of central sensitization discussed here is related to changes in the spinal cord dorsal horn. A number of pre- and postsynaptic mechanisms are involved; importantly, an ongoing, repetitive C-fibre input is required to instigate the response. In the context of injury, C-fibre firing is initially triggered by the injury or trauma event, but once there is no longer any peripheral input this response is not sustained. Peripheral immune activation may sustain a mild peripheral C-fibre activation in some patients, long after trauma, although the reasons why only some patients might develop such activation remain largely unknown.

Randomized controlled trials (RCTs) are currently ongoing to investigate further the preliminary evidence that immunoglobulin G (IgG) may be an effective treatment for some chronic pain conditions. In October 2012, experts in this field gathered at a workshop to exchange their experience 5. Participants summarized evidence supporting IgG use not only in CRPS but also in diabetic lumbosacral radiculoplexus neuropathy, diabetic neuropathic pain, Sjögren's syndrome-associated neuropathy, fibromyalgia and postpolio syndrome.

Recent evidence suggests that placebo responses in chronic pain conditions are generally small; in data derived from systematic reviews and meta-analyses, the highest average placebo response by a considerable margin is in diabetic polyneuropathy (‘neuropathic pain' = pain arising as a direct consequence of a lesion or disease affecting sensory nerves) (22%). In postherpetic neuralgia, the placebo response rate is 12%; in fibromyalgia 7% and in long-standing CRPS 0–6%.

The main outcome for pain trials is the pain intensity as rated by a patient. This is usually performed on a 100-point visual analogue scale (VAS) or a 10-point numerical rating scale (NRS), where 0 = ‘no pain’ and 100 or 10 = ‘pain as bad as you can imagine’. On the 10-point scale, 0–3 is considered mild, 4–6/7 moderate and 7/8–10 severe pain. Two NRS points is considered a clinically meaningful reduction in pain.

Currently, the only published RCTs investigating the use of IVIg in chronic pain conditions have been in CRPS and postpolio syndrome. A cross-over RCT in 12 CRPS patients measuring responses to placebo and to 0·5 g/kg (low-dose) IgG revealed that, consistent with open trials conducted previously, 25% of subjects (n = 3) experienced >50% pain relief after IVIg treatment; no patient had such a response after placebo 6. This raises the question of how to predefine which patients will respond to IgG treatment; economically, however, it may be viable to provide a ‘diagnostic’ treatment dose, and then continue to treat responders.

With regard to maintenance treatment, earlier attempts involved patients receiving IVIg treatment repeatedly, whenever their pain had peaked, rather than being treated continuously, but this regimen never induced ‘remission’ 7. It has been shown, however, that remission may be achieved through continuous IgG treatment; a further study 8 used low-dose SCIg in two patients with long-standing CRPS (5–6 years) for 3 and 12 months, respectively, who had responded to initial IVIg ‘induction treatment’. Not only was considerable pain relief sustained during the SCIg treatment period, but at follow-up 12 months after final SCIg infusion these patients had not experienced a return of their symptoms.

The quality of life (QoL) of patients with some chronic pain conditions is very low, which means that even though treatment (including IgG) may be expensive it could also be cost-effective, as pain has a major impact on QoL scales such as EQ-5D.

With the low efficacy of current treatments, pain management programmes are needed to help patients cope with their condition and achieve a reasonable QoL. Chronic pain management does not just involve pain relief; psychological interventions are also needed, as most patients who have chronic pain for longer than 6 months may suffer from anxiety and/or depression. Physical rehabilitation is also important, as people with chronic pain often restrict their movement to try and reduce the discomfort, but in a vicious cycle inactivity then leads to even more pain. Anti-convulsants or antidepressants are also used, and spinal cord stimulation has been used for regional pain syndromes such as CRPS. This involves placing an epidural electric lead and implanting a pulse generator under a muscle; this is then controlled by the patient with a magnet, generating a comfortable pins-and-needles sensation in place of the pain. A third of patients who undergo this procedure will have complications or require reoperation, but nevertheless it is considered cost-effective in the United Kingdom for certain conditions. The cost-effectiveness of this expensive treatment underscores the consideration that low-dose IgG may well become a cost-effective treatment for some chronic pain conditions in the future, if efficacy can be confirmed in RCTs. Following the promising results of the preliminary studies 4,6,7, funding has been granted by the UK government for a RCT in 108 CRPS patients across seven UK centres (ISRCTN42179756).

An international immune-modulation registry is currently being established in an attempt to understand these effects more clearly.

Disclosure

A. G. has received grant support, travel support, speaker fees and consultancy fees from CSL Behring, Biotest, BPL, Baxter, Grifols, Asxome and Pfizer.