BACKGROUND: Decisions on the intensity of analgesic therapy and judgments regarding its efficacy are difficult at the end of life, when many patients are not fully conscious and pain is a very common symptom. In healthy individuals and in postoperative settings, nociception and subsequent pain relief have been shown to induce changes in the autonomic nervous system (ANS), which can be detected by measuring heart rate variability (HRV). OBJECTIVES: The changes in the ANS were studied by measuring HRV during opioid therapy for cancer breakthrough pain (CBTP) in palliative-care patients with cancer and compared these changes with patient-reported pain levels on a numeric rating scale (NRS). PATIENTS AND METHODS: The study included ten patients with advanced cancer and baseline opioid therapy. In each patient, a 24-hour peak-to-peak HRV measurement with a sampling rate of 4,000 Hz was performed. High frequency (HF), low frequency (LF), total power, pNN50 (indicating parasympathetic activity), and log LF/HF were obtained in two intervals prior to therapy and in four intervals thereafter. Intensity of CBTP was recorded using a patient-reported NRS prior to therapy and 30 minutes afterward. RESULTS: CBTP occurred in seven patients (three males and four females; mean age: 62 ± 5.2 years) and was treated with opioids. A highly significant positive correlation was found between opioid-induced reduction in patient-reported pain intensity based on NRS and changes in log LF/HF (r > 0.700; p < 0.05). Log LF/HF decreased in patients who had a reduction in pain of >2 points on the NRS but remained unchanged in the other patients. CONCLUSION: Our data suggest that log LF/HF may be a useful surrogate marker for alleviation of CBTP in patients with advanced cancer and might allow detection of pain without active contribution from patients.