Pandora's Box - Opportunities and Dangers of Pain Therapy

Pain management in tumor patients has become more complex in recent years. The WHO staging scheme has since undergone various modifications. In addition to medications, psychological interventions and physical therapy should always be considered.

Tumor diseases are often associated with pain. Thus, about 75% of all tumor patients suffer from pain [1]. Approximately 30-60% of these patients report their pain as severe to very severe [2,3].

The WHO staging scheme – old hat?

The gold standard for the treatment of tumor pain is considered to be the WHO staging scheme, which was introduced as early as 1986. For example, Zech et al. [4] show that after only six days of correct application of the WHO staging scheme, about 90% of patients had little to moderate pain. And yet, about 10% of patients continued to suffer from severe to very severe pain even after one month and until death, despite correct application of the regimen. Moreover, the more recent literature assesses the success rate of the classic WHO staging scheme much more critically, with highly variable response rates ranging from 15 to 75% [1]. This has prompted various proposals for modification, especially in recent years (Fig. 1).

Also worthy of discussion is the fact that the WHO staging scheme focuses exclusively on drug therapy for tumor pain and disregards other treatment strategies [5]. Thus, advanced therapy options for drug treatment are often not even considered by treatment teams.

Especially for locoregional pain, it should be remembered that many patients can be helped efficiently and in the longer term with infiltrations with little to no systemic side effects [6]. Often, such an intervention can reduce or, at best, even completely suspend systemic drug analgesia, which has many side effects. Simple topical applications such as local anesthetic gels/patches and secondary transdermal capsaicin applications should not be forgotten.
Various tumor pain experts [5,7] also suggest skipping the second stage (weak opioids) and moving directly to the third stage (strong opioids) if the first stage is insufficiently effective. This is also consistent with our clinical approach.

For several years, co-analgesics such as antidepressants and pentinoids have also had their place in the treatment of tumor pain. The best Numbers Needed to Treat (NNT) are achieved by the old tricyclic antidepressants (NNT 3.6), especially for neuropathic pain [8]. Among pentinoids, gabapentin has the better side effect profile than pregabalin (Number Needed to Harm, NNH, of 25.6 vs. 13.9) according to a recent review [8].

The analgesic effect of paracetamol is often overestimated for severe pain. Paracetamol is a weakly effective analgesic [9,10], so little therapeutic benefit is expected for severe pain.

Very important are psychosomatic aspects, which play at least as big a role in tumor patients as in patients with chronic benign pain [11,12]. Pain education, teaching strategies to better manage pain to hypnotherapy [13] should be considered and implemented in close coordination with psychooncology.

Of course, palliative radiotherapy should always be considered as well. This is particularly true for bone metastases: Here, a response rate of approx. 60% can be achieved with regard to pain relief [14]. Locoregional therapy options should be considered, especially in cases of severe pain, until the analgesic effect of radiotherapy sets in.

Targeted physical therapy is also usually very helpful [15] and is strongly recommended by the authors.

Pandora’s Box Part One: Opioid Efficacy

In the treatment of chronic benign pain, the prescription of opioids has been strongly questioned in recent years [16,17]. The reason for this is doubt about the positive benefit-risk profile of opioids. A recently published review from Germany concluded that the NNT of opioids for chronic low back pain at four weeks was 19, and the NNH was 6 (discontinuation due to severe side effects) [18]. A recent Cochrane analysis [19] reported an overall adverse event rate of 78% as well as 7.5% serious adverse events.

Nevertheless, the consumption of legally prescribed opioids has increased alarmingly worldwide – most notably in the USA [17], but also in Switzerland [20] and in neighboring countries such as Germany [21]. Likewise, the potential for addiction was significantly underestimated and/or ignored [22].

In our clinical work with tumor patients, we repeatedly experience cases in which opioids do not lead to pain relief despite adequate dose increase as well as opioid rotation, especially in neuropathic as well as movement-dependent pain patterns. We are not aware of systematic studies on the incidence of opioid-insensitive pain in tumor patients. After all (as already mentioned), the success rates of the classic WHO staging scheme, in which opioids play a supporting role, are nowadays judged more critically than in the past [1].

Since opioids lead to a decrease in quality of life even at low doses [17], it should also always be carefully examined in tumor patients whether a therapeutic benefit of opioid therapy exists at all and is in reasonable proportion to the side effect profile.

Pandora’s Box Part Two: Long-Term Survivor

The average percentage of patients with chronic pain after tumor therapy ranges from 28% [23] to 55% depending on the literature [1], but can vary depending on the tumor type and can be significantly higher (breast carcinoma: 84%) [24]. In addition, thanks to innovative immunochemotherapies, more and more tumor patients are surviving in the medium and long term. Thus, about two-thirds of those suffering from a tumor survive the first five years and about 40% survive the first ten years [25]. Often, these long-term survivors are treated with (sometimes high) doses of opioids during the acute phase of their tumor disease (Fig. 2). We are also seeing more and more long-term survivors with tumor therapy-induced pain (postoperative chronic pain, chemotherapy- and radiotherapy-induced chronic pain), who are often treated with opioids. Why – according to the logical question – should “long-term survivors” benefit more from chronic opioid therapy than patients with a chronic benign pain condition? Are loss of efficacy, quality of life decreasing side effects, and addiction development only relevant for benign chronic pain?

The scientific answers are lacking, but differences between benign and tumor-associated pain are not expected to exist. The question of whether perioperatively administered opioids lead to a worse quoad vitam outcome in tumor patients has also not been conclusively answered: In vitro [26] as well as in animal studies [27] there are indications of this, but no randomized-controlled studies exist yet.

Take-Home Messages

Pain management in tumor patients has become increasingly complex in recent years.
In addition, the WHO staging scheme has undergone various modifications, which is why the expertise of a broadly trained pain therapist should be sought in cases of persistent pain despite correct application of the scheme. Ideally, this person has profound knowledge of drug, interventional and psychosomatic therapy.
In addition to drug analgesic therapy, psychological interventions, infiltrations, radiotherapy, and physical therapy should always be considered. Close interdisciplinary and multiprofessional cooperation with oncologists, the family doctor, palliative physicians, radio-oncologists, psychooncologists and, depending on the tumor condition, other specialist disciplines is an indispensable basis for offering the patient the best possible pain therapy.
In particular, “long-term survivors” present new pain management challenges to treatment teams, especially with regard to opioid therapies.

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