By Palanisamy Vijayanand
There are Indian TV channels, whose business model is based on recruiting your kid for junior reality shows, train them to become VJ’s, get them a leg-up in movies, get them married, humour them with awards (best dentistry in a backup dancer award), and telecast all this for a profit. Such one-stop solutions, when it gets too painful to watch, always have the option of switching off the TV. Such anodyne ‘art’ (if you would call it that), presented with all the persuasive skills and battering psychological hype that can be bought, has the distinct advantage over science in matters of national importance. But science, too, can tell us useful stories that provide us information and knowledge needed to create health. One such story is the recently published systematic review of therapeutic interventions to prevent persistent pain following surgery. It is a predicament which has no one-stop solution, has no option of switching off, and has no anodyne which works well enough.
With a sound search strategy and rigorous criteria, Humble and colleagues shortlisted thirty two randomized controlled trials in adults undergoing procedures with a high risk of nerve injury or transection which might result in persistent pain – amputation (pain: 50–80%), mastectomy (pain: 20–40%) and thoracotomy (pain: 30–50%). These studies on preventive therapeutic interventions are based on the fact that the peak noxious barrage due to the neural trauma associated with these operations occur perioperatively; and on the assumption that reducing such noxious input, with prompt, aggressive management, has the potential to reduce the risk of chronic pain.
The heterogeneity of trial methodology and outcome measures ruled out a meaningful meta-analysis. A number of trials studied a single, brief intervention, which was typically not enough to achieve long-term benefits, potentially due to the fact that the process of neuroplasticity could continue for days or weeks post-operatively. The outcome measures varied between studies – visual analogue scale (VAS; 0–100 mm), numerical rating scale (NRS; 0–10), and verbal rating score (0–3 = nil/mild/moderate/severe) were all used. Pain at rest and movement was assessed in some, quantitative sensory testing was used in some, and a multidimensional score such as the McGill Pain Questionnaire was used in some other. The mean sample size was 89 (±12 SD) subjects (range 36–343), and the mean duration of patient follow-up in the trials was 7 (±1 SD) months following the surgical procedure (range 2–15). Despite the lack of consistency and comparability between trials, several consistent themes emerge in the results.
Gabapentinoids and antidepressants
In mastectomy, gabapentinoids reduced acute pain and reduced the overall incidence of chronic pain and the incidence of chronic burning pain. Gabapentin did not reduce acute pain where epidural analgesia was used for amputation or thoracotomy. In the former, therapeutic doses of gabapentin were used, but the patients had chronic pain preoperatively secondary to vascular disease. In the latter, only a single dose of gabapentin was given perioperatively. The antidepressant Venlafaxine (37.5 mg) was associated with significantly lower post-mastectomy pain after 7 days, and after 6 months the incidence of post-mastectomy burning and stabbing pain was significantly lower. Within the trials, gabapentinoids were often given once only or at sub-therapeutic doses. However, if an appropriate therapeutic dose was administered for a longer period of time, the efficacy appeared greater. Vascular patients with chronic pain preoperatively continued to have chronic pain post-operatively despite gabapentin.
Local anaesthetics and regional anaesthesia
Regional analgesia was beneficial for reducing perioperative pain and subsequent chronic symptoms. The single trial that found epidural analgesia to be no better than standard analgesia comprised vascular patients with pre-existing chronic pain prior to amputation. With regards to pre-emptive effect, epidural analgesia reduced acute and chronic pain versus control therapy after thoracotomy and amputation. A complex trial indicated the benefits of early epidural insertion and continued infusion for the entire perioperative period. One trial found that it made no difference to acute or chronic pain whether the epidural was commenced immediately before or after the thoracotomy procedure. In contrast, three trials found that the optimization of analgesia preoperatively had a beneficial impact on both acute and chronic pain. Regional anaesthesia was particularly useful in patients who were opioid tolerant. Optimal duration of regional analgesia is yet to be determined and potential benefits may be lost if epidural infusions are discontinued too early for logistical reasons.
Infiltration of local anaesthetic could provide a brief period of analgesia, but did not impact on the risk of developing chronic pain. Ropivacaine infiltration reduced acute pain for 1.5 and 6 h, respectively, but had no impact on the development of chronic post-mastectomy pain. In another trial, the drug had no impact on acute or chronic pain. Lidocaine infiltration had no impact on acute or chronic pain in thoracotomy patients. In contrast, intraoperative intravenous lidocaine and perioperative EMLA cream reduced the incidence of chronic pain following mastectomy, without making a significant impact on acute pain. How about paravertebral block in mastectomy? One trial found that paravertebral block significantly reduced acute pain and chronic pain 1 year later compared with sham block, while another found that paravertebral block had no significant impact on acute pain, but reduced the prevalence of chronic pain, compared with control.
Remifentanil and propofol
A trial comparing preoperative epidural commencement with low-dose intravenous remifentanil infusion versus postoperative epidural commencement with a high-dose intravenous remifentanil infusion for thoracotomy patients found no difference in acute pain. But, high-dose remifentanil was associated with a higher incidence of chronic pain. In addition, they found that the surface area of chest wall allodynia was significantly larger for the high-dose remifentanil group during the first post-operative month, confirming the theoretical concept of opioid-induced hyperalgesia. TIVA with propofol and remifentanil was associated with a reduced incidence of chronic post-thoracotomy pain than inhalational anaesthesia with sevoflurane. Given the phenomenon of opioid-induced hyperalgesia, the potential benefit of TIVA is more likely to be propofol–mediated, potentially via glutamate, GABA-A and glycine receptors
Ketamine and cryoanalgesia
Intravenous ketamine infusion significantly reduced acute pain after thoracotomy but did not reduce chronic pain. It had no impact on acute or chronic pain with or without the presence of epidural analgesia for amputation or thoracotomy. In thoracotomy patients, intercostal cryoanalgesia had no impact on acute pain. Of the five thoracotomy trials, intercostal cryoanalgesia had no impact on chronic pain in one trial and actually increased chronic pain in four trials.
Acute neuropathic pain is an eminently treatable, but significantly under-recognized condition. The incidence of acute neuropathic phantom limb pain after amputation is greater than 50%. If perioperative pain management regimes only incorporate opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and regional analgesia, then patients with acute neuropathic pain may be undertreated and therefore at significantly increased risk of developing chronic pain. Using simple screening tools such as DN4 or LANSS to identify those who experience a disproportionate level of pain, would help institute interventions that may provide superior analgesia and facilitate optimum recovery. Moreover, some pharmacological agents may take a number of days or weeks to be of benefit and therefore therapeutic dosages should be used for several weeks in many instances. Furthermore, neuropathic symptoms may take several days to manifest post-operatively, thus emphasizing the importance of recognition and referral to a vigilant and cognizant acute pain service. This may decrease the burden on society and the amount of financial resources spent on the management of chronic pain. Unlike a career in television, the therapeutic options available for established chronic pain have substantial limitations and problematic side effects. Preventative techniques are of particular importance.
Conflict of Interest: Dr. Stephen Humble, the first author of the paper, was my contemporary during training in Pain Medicine in Australia. Him at Perth. Me at Brisbane. It has been a thoroughly enjoyable experience writing a post on his paper.